The nervous system Major differences between nervous system and other organ systems of the human body: 1. Topographic localization - specific areas (cerebral centers) - even small focal lesion may cause selective severe dysfunction - variable neurologic deficits (dependent on location) - e.g. frontal cortex Χ spinal cord 2. Protective mechanisms - skull - protection from trauma Χ vulnerability to intracerebral expansions, edema, etc. - CSF - protection Χ can cause hydrocephalus 3. Limited spectrum of pathologic responses to injury - e.g. glial response is similar in various lesions (infarction, trauma, degeneration) 4. Specific diseases - majority of pathologic processes are similar to other organs (infections, ischemia, etc.) - some disorders are specific to neural tissue (e.g. neurodegenerative processes) Cells of nervous system and their behaviour in pathologic processes • Neurons heterogenous family no postembryonic multiplication or regeneration most common - necrosis (nucleus - pyknosis, karyorrhexis, karyolysis; cytoplasm - chromatolysis=tigrolysis (loss of Nissl substance) - infections (intraplasmatic inclusions) • Astrocytes major supporting cell in an injury - gemistocytic astrocytes (Gr. gemistos=full) - production of dense network of cellular processes (analogous to fibrous scar) - no collagen! - glial scar Rosenthal fibres - eosinophillic intracytoplasmatic refractile fibres - reaction to slowly growing expansile lesions corpora amylacea - accumulation of glycoproteins in cell processes - sign of aging • Oligodendrocytes satelite cells around neurons - processes wrap around axons - myelin; lymphocyte-like nuclei loss of myelin in acquired demyelinating disorders (e.g. multiple sclerosis) • Ependymal cells lining of ventricles - closely related to chorioidal cells loss of e. cells - proliferation of supependymal glial cells - ependymal granulations infections - CMV - viral inclusions • Microglia derived from circulating monocytes most important phagocytic cells in CNS phagocytosis of lipids - gitter cells; elongation of nuclei - rod cells; in viral infections - accumulation - microglial nodules Edema, herniation and hydrocephalus rigid compartment (skull, vertebral column, dura mater) brain parenchyma (P), blood (B), CSF (C) P+B+C=constant Cerebral edema more appropriately = brain parenchymal edema vasogenic cytotoxic • vasogenic disruption of integrity of the blood-brain barrier escape of fluid from vasculature into interstitial space (interstitial edema) no lymphatic vessels! - no drainage! localized (periphery of abscesses or tumors) or generalized • cytotoxic intracellular edema - due to cellular injury - e.g. hypoxia-ischemia Clinically: headache, edema of N.II. papilae, vertigo, vomiting, coma, death Grossly: increased weight (1500+ g) brain overfills cranial cavity, gyri are flattened, sulci are narrowed, ventricles compressed herniation occurs Herniation increased intracranial pressure - brain is "too large" for the cranial cavity type of herniation depends on location of expansion 1. Transtentorial (uncinate) herniation medial aspect of temporal lobe is compressed against the free margin of tentorium cerebelli N.III. is compressed - ocular manifestation posterior cerebral artery is compressed - secondary ischemic injury (visual cortex) 2. Subfalcine (cingulate) herniation unilateral asymmetric expansion within cerebral hemisphere displacement of cingulate gyrus under the falx cerebri compression of branches of anterior cerebral artery 3. Tonsillar herniation displacement of cerebellar tonsils through the foramen magnum life threatening - brain stem compression, compromises vital respiratory centers hemorrhagic lesions in the midbrain (secondary brain stem (Duret's) hemorrhages) Hydrocephalus CSF produced by choroid plexus - circulation (foramina Luschka and Magendie) - absorption by arachnoid granulations hydrocephalus = accumulation of excessive CSF within ventricular system decreased resorption (majority of cases) or overproduction noncommunicating h. - obstruction of the flow of CSF within the ventricles (tumors of aqueductus Sylvii, postmeningitic stenosis) communicating h. - obstruction of the flow of CSF in subarachnoid space or in granulations before closure of cranial sutures - enlargement of the head, increase of head circumference after closure of cranial sutures - enlargement of the ventricles, increased intracranial pressure h. ex vacuo = dilatation of the ventricular system (secondarily) due to loss of brain parenchyma - compensation; flow of CSF remains normal Vascular diseases normally - 15-20% of cardiac output - very sophisticated system of autoregulation of perfusion ischemia - irreversible parenchymal injury within brief period (5 min) vascular insults - 3rd most common cause of death (USA) 3 major categories: • global hypoxic-ischemic encephalopathy • infarcts • hemorrhages Global hypoxic-ischemic encephalopathy brain is sufficiently perfused even in severe hypotension (50 mm Hg systolic) hypoxia=decrease in the O2 Χ ischemia=decrease of tissue perfusion most susceptible - neurons (namely pyramidal cells of hippocampus, Purkinje cells of cerebellum) high risk areas = at junctions of arterial territories (watershed areas) morphology of changes depends on severity of ischemia and duration from injury first changes visible only after 12-24 hrs. (patient must survive this period!) Grossly: edema, softening, irregular discoloration, areas of hemorrhage, laminar cortical necrosis later on - patient maintained on respiratory support - brain death - body survives, in brain progression of necrosis - "respirator brain" - swollen, dusky and soft fate of the patient depends on degree of ischemia (only confusion - coma - loss of cortical functions - death) Micro: neuronal shrinkage or swelling, eosinophilia, nuclear pyknosis; in neuropil - perivascular and pericellular empty spaces (sign of edema) later stages - cleaning of necrosis (gitter cells), perifocal gliosis - postmalatic pseudocyst Infarcts local circulatory disturbances most common form of cerebral vascular disease (80% of "strokes") 7th decade, M>F arterial occlusion atherosclerosis + thrombosis - most comm. = int. carot. a., basilar a. embolism (from heart [endocarditis, atrial thrombi], proximal segment of carotid a., paradoxic thrombembolism [f. ovale]) - most common target = intracerebral blood vessels (middle cerebral a.) Extent, distribution and clinical symptoms influenced by: site of arterial occlusion, time span of development, presence of anastomoses (circle of Willis), systemic perfusion pressure Grossly (irrespective of causes and location): first changes after 6-12 hrs - softening, pale discoloration, blurring of borders full blown appearance - 2-3 days - liquefaction - malacia; sharper demarcation after 1Mo - cavitation (postmalatic pseudocyst) Clinical symptoms sudden onset preceded by transient episodes of neurologic dysfunctions - Transient Ischemic Attacks (TIAs) TIA = important predictor of stroke 1/3 of patients with TIAs develops infarcts symptoms caused by: infarct itself, perifocal edema, herniation contralateral hemiparesis & spasticity loss of sensation visual field abnormalities speech abnormalities (aphasias) - if dominant hemisphere is involved small infarcts in basal ganglia - slowly progressing symptomatology status lacunaris, status cribrosus Intracranial hemorrhages epidural subdural subarachnoid intraparenchymal Epidural hematoma rupture of meningeal artery (skull fracture) middle mening. a. expansion - compression of brain + herniation rapid progression - immediate surgical drainage! lucid interval between trauma and progressive loss of consciousness Subdural hematoma disruption of bridging veins (brain-dural sinuses) rapid change of head velocity (blows to the head, violent shaking) mainly at cerebral convexities acute - slowly progressing - clotted blood chronic - in atrophic brains - no acute symptoms - decomposition of blood - osmotic enlargement - slowly progressive neurological symptoms confused clinically with dementia, Alzheimer's disease Subarachnoid hemorrhage less frequent than intraparenchymal hemorrhage not associated with trauma most common cause - rupture of saccular (berry) aneurysm, less commonly A-V malformation 1% of population (more common in certain disorders - polycystic kidney disease, coarctation of aorta, A-V malformations of the brain) more frequent in arterial hypertension location - bifurcation of branches of internal c. a. - defect of elastic lamina multiple in 25% of pts. size mm-cm highest risk of rupture = 4-7 mm (beyond this size likelihood of rupture decreases) larger aneurysms - mass effect subarachnoid bleeding - usually not massive - leakage! arterial spasms - infarcts (40%) - 4.-9. day Clinical features F>M, <50's increased pressure (lifting heavy things, defecation) abrupt onset, headache, nausea, vertigo, coma bloody CSF, meningeal signs (neck rigidity) 50% acute mortality tendency to recurrence Combined intraparenchymal and subarachnoid hemorrhage A-V malformations=clumps of vessels arteries+veins intrahemispheric or on the surface of hemisphere bleeding in 10's-30's Intraparenchymal hemorrhage traumatic Χ spontaneous mid- to late adult life (peak 60Y) most common cause = hypertension (<50% of cases) 15% of patients with hypertension die because of brain hemorrhage HT => atherosclerosis, arteriolosclerosis, necrosis of arterioles Charcot-Bouchard microaneurysms rupture - intraparenchymal bleeding vessels <300΅m in basal ganglia other causes: systemic coagulation disorders open heart surgery neoplasms vascular diseases (amyloid angiopathy, vasculitis, berry aneurysms, A-V malformations) Grossly basal ganglia (putamen, external capsule), thalamus, cerebral white matter, pons, cerebellum brain is asymetrically distorted - mass effect - herniation dissection into ventricles and/or subarachnoid space no or sparse necrosis pseudocyst - hemosiderin in the wall Clinical symptoms stroke - abrupt onset severe headache, vomiting, loss of consciousness - coma CNS trauma epidural hematoma subdural hematoma traumatic parenchymal injuries Concussion transient loss of consciousness, widespread paralysis, seizures recovery over hours to days loss of memory about the trauma no anatomic lesion! Diffuse axonal injury cause of posttraumatic dementia or persistent vegetative state result of sudden angular acceleration/deceleration stretch of nerve cell processes grossly - no changes! (rarely minute areas of hemorrhage) Contusion result of blunt trauma lacerations (tearing) and hemorrhages in the superficial brain parenchyma traumatic subarachnoid hemorrhage microscopically - small hemorrhagic infarcts any place, most common=frontal poles, temporal poles, occipital poles, posterior cerebellum skull is usually intact! healing by glial scar, hemosiderin deposits common cause of seizure activity Complications posttraumatic edema (herniations, secondary infarcts) infections, licquorrhea posttraumatic hydrocephalus seizures Infections 2 factors - 1. nature of the infectious agent (rabies, HSV I) 2. integrity of normal host defenses (skull fracture) bacteria, viruses, fungi, higher organisms (amebae, parasites) meninges+CSF = meningitis brain parenchyma = encephalitis meninges -> brain = meningoencephalitis localized (abscess, poliomyelitis) Χ generalized (bacterial leptomeningitis) Gates of infection blood - hematogenous nerves - neurotropic (HSV, rabies) trauma - direct infection ear - otogenic (mastoiditis, ottitis media) paranasal sinuses (frontal sinusitis) puncture - iatrogenic (lumbal pucture) (Lepto)Meningitis arachnoid+pia mater+subarachnoid space rapid spread via subarachnoid space - generalization • purulent (usually bacterial) • lymphocytic (viral) • chronic (bacterial, fungal, amebic) Purulent meningitis Etiology: newborns - E. coli (neural tube defects!) children - H. influenzae (vactination!), Str. pneumoniae young adults - N. meningitidis (small epidemies - army, holiday camps) old adults, posttraumatic - Str. pneumoniae, G- bacilli Grossly meninges are congested, edematous, opaque exudate in subarach. space (pus, fibrin) - yelowish colour distribution varies - pneumococcal m.=convexities Χ hemophilus=basilar exudate congestion and edema of the brain and spinal cord most severe cases - ventricular ependymitis + pyocephalus Microscopically leptimeninges+subarachnoid space filled by purulent exsudate (neutrophils, fibrin, bacteria) Clinical features fever, general symptoms (fatigue, ...) meningeal signs - headache, stiff neck, altered mental status, photophobia) CSF is turbid, neutrophils, protein, glucose levels are decreased, bacteria prognosis depends on rapidity of diagnosis & antimicrobial treatment late complication = meningeal adhesions - hydrocephalus Lymphocytic meningitis usually of viral origin (so called "aseptic") self-limited, much better prognosis - spontaneous healing, no complications any viral infection (most frequent mumps, echo-, coxackie-, EBV, HSV) sometimes associated with concurrent encephalitis clinically similar to bacterial m. - less severe symptoms CSF - lymphocytes, slightly elevated protein, glucose normal Chronic meningitis bacteria (TB!, Brucella, Treponema pallidum) and fungi (Cryptococcus neoformans - AIDS!) slower development Grossly - basilary meningitis Microscopically - lympho, plasma cells, macrophages (TB - Orth's cells), fibroblasts, granulomas, caseous necrosis (TB) Clinically - headache, stiff neck - may be absent! CSF - mononuclear cells, increased protein, decreased glucose Complications - adhesions, hydrocephalus, endarteritis (intimal proliferation with subsequent occlusion of lumen) - infarcts Parenchymal infections localized (abscess, tuberculoma, toxoplasmosis) generalized (viral encephalitis) Brain abscess wide variety of bacteria (Staphylococci, Streptococci, anaerobes) hematogenous spread - from elsewhere in the body (endocarditis, lung abscesses, bronchiectasis, osteomyelitis) contiguous spread - adjacent foci of infection (otitis media, sinusitis) direct implantation - trauma most commonly - cerebral hemispheres (temporal and frontal lobes) solitary or multiple enlargement - mass effect; symptoms according to localization misdiagnosed as a tumor cavity filled by thick pus (yellow-green), delimited by pyogenic membrane (layer of granulation tissue, richly vascular) surrounding parenchyma edematous, congested reactive astrocytes Viral encephalitis almost always spread from extracerebral sources (varicella-zoster; rabies) almost always also infection of meninges - lymphocytes in CSF histologically - most characteristic = lymphocytic perivascular infiltrates (cuffing) + microglial nodules + neuronophagia (necrosis and fagocytosis of individual neurons) + sometimes viral inclusions (Negri bodies in rabies, CMV inclusions) specific feature = tropism of certain viruses (zoster - ggl. cells of posterior ganglia; poliomyelitis - anterior corns of spinal cord) certain viruses cause latent infections - hidden for many months to years - reactivation - infection 2 groups: 1. acute viral infections 2. slow viral diseases Acute viral infections (pan)encephalitis, meningoencephalitis arthropode-borne (arbo) viruses - mosquitoes, ticks perivascular infiltrates, microglial nodules regional epidemies - eastern and western equine, Venezuelan, St. Louis, California encephalitis frequently fatal Herpetic infections (HSV I, II) necrotizing, hemorrhagic inclusion bodies! children (newborns), young adults fatal, in survivors - dementia, loss of memory encephalitis may accompany other common infections - measles, rubella, chickenpox, mumps and also in AIDS (both HIV and opportunistic infections) Slow virus diseases very long latency, slow progression Subacute sclerosing panencephalitis (SSP) children and young adults following measles, rarely after vaccination clinically - changes of the personality, slow progression to death histologically - neuronophagia, gliosis Progressive multifocal leukoencephalopathy (PML) JC virus (no relation to Creutzfeld-Jacob disease!) slowly evolving encephalopathy, in immunocompromised (AIDS, leukemias, immunosupression, TB) virus infects oligodendroglia - areas of demyelinization slow progression of neurologic symptoms, no treatment Subacute spongiform encephalopathy (Creutzfeld-Jacob) rapidly progressing dementia (months-several years) -> death very rare (1:1Mio) sporadic and familial forms etiologic element = prion (PRotein infectION) - protein with abnormal tertiary structure exact mechanism of development is unclear closely related to other prion diseases (scrapie, kuru (N. Guinea), mad cow disease) histology - cerebral cortex - bubbles and holes (spongiform encephalopathy) Other CNS infections protozoal - malaria, toxoplasmosis (pseudocysts in AIDS), amoebae, ricketts, parasites Tumors some specific features irrespective of dignity (ben/mal) similar clinical symptoms sometimes localization is more important than biological behavior (ependymoma of IV. ventricle - respiratory centre!) Tumors of neuroepithelial tissue Astrocytic tumors wide range of neoplasms differ in location, age and gender distribution, morphological features, growth potency tendency to dedifferentiation in recurrent tumors Astrocytoma diffuse infiltration of margin - local infiltrative growth - difficult operative treatment younger adults several cm - infiltration via commissures into contralateral hemisphere Histology: Fibrillary astrocytoma Gemistocytic astrocytoma Anaplastic astrocytoma - increased cellularity, distinct nuclear atypia and marked mitotic activity Glioblastoma multiforme poorly differentiated hemorrhage, necrosis - inhomogenous structure marked nuclear atypia and mitotic activity, prominent neovascularisation and necrosis with pseudopalisading of tumor cells dismal prognosis (average survival 8-10M) Oligodendroglioma less frequent (5% of all glial tumors) well-differentiated, diffusely infiltrating adults, cerebral hemispheres tumor cells with rounded nuclei microcalcifications (X-rays!) Ependymoma cerebral ventricles, central canal of the spinal cord children and young adults (first two decades) presents by blocking CSF - no possible operation rosettes ( columnar cells arranged around a central lumen) Choroid plexus papilloma Choroid plexus carcinoma Medulloblastoma malignant infantile invasive tumor of cerebellum (vermis, later hemispheres) neuronal differentiation metastasizes via CSF (implantations on ventricular ependyme and in subarachnoid space) Meningioma slowly growing benign tumor attached to dura mater - ventral poles of cranial cavity (falx, convexity, sphenoidal bone) adults, predominance for females usually solitary, rarely multiple invasion of bone (not a sign of malignancy) whorls and psammoma bodies (Ca2+) impression of brain parenchyma Pinealoma, pinealoblastoma Metastatic tumors of the CNS carcinomas (lungs, breast) melanoma choriocarcinoma renal clear cell carcinoma multiple lesions, sharp circumscription, spheric, collateral edema Degenerative diseases Diseases of myelin Multiple sclerosis young adults, peak incidence 18-40Y waxing and waning neurological abnormalities different regions, progression over many years visual disturbances (blurred vision, diplopia, scotomata) paresthesias, spasticity of extremities, speech disturbances, gait abnormalities pathogenesis not fully understood autoimmune disease? environmental+hereditary factors Grossly: external appearance of brain and spinal cord - normal cut section - areas of demyelinization (plaques) plaques anywhere - common sites = periventricular areas, optic nerves, spinal cord early lesions pink&soft, chronic ones gray&firm Microscopically: areas of demyelinization starts in perivenous regions variable perivascular lymphocytic infiltrate Metabolic and toxic disturbances nutritional - avitaminosis B1, B12 B1 (thiamin) Wernicke-Korsakoff sy (encephalopathy+psychosis) accompanied by peripheral neuropathy alcoholics! B12 (cobalamin) pernicious anemia, peripheral neuropathy subacute degeneration of spinal cord (dorsal and lateral white columns) Poissoning lead (Pb), mercury (Hg), arsenic (As) industrial chemicals medicaments irradiation alcohol (acute, chronic-Wernicke-Korsakoff sy) Metabolic disorders =metabolic encephalopathy hyperglycaemic coma uremia portotsystemic encephalopathy - hepatic coma M. Wilson (hepatolenticular degeneration) phenylketonuria Neuronal degenerative disorders unknown origin similar clinical presentation selective lesion of one or several functional systems, others uninvovlved (e.g. Parkinsons disease - striatum and ncl. niger) symetric, progressive course inherited or sporadic involvement of cortex - dementia (Alzheimer, Pick) involvement of basal ganglia - extrapyramidal symptomes (rigidity, tremor) (Parkinson, Huntington) spinocerebelar degeneration (Friedreich ataxia) motoric neurons (ALS, Werding-Hoffman) Alzheimer's disease most common cause of dementia in elderly (50Y) sporadic, in 10% family history cause remains unknown factors associated with development: genetic factors, deposition of amyloid (amyloid precursor protein-APP) Morphology usually brain atrophy (frontal, temporal, parietal lobes) symetrical dilatation of lateral ventricles hydrocephalus ex vacuo Micro: neurofibrillary tangles (coarse filamentous aggregates within cytoplasm of neurons) - hippocampus, basal forebrain, neocortex and brain stem senile plaques - aggregates of tortuous coarse neurites in the neuropil of cerebral cortex, sometimes with amyloid core amyloid angiopathy only if numerous lesions are present - diagnosis of AD Parkinsonism disturbance in motor neuron functions rigidity, expressionless face, stooped posture gait disturbances, slowing of voluntary movements, pill-rolling tremor James Parkinson 1817 (1st descr.) Awakenings (R. deNiro) • idiopathic - progressive, 5-8th decade • parkinson sy lesion of dopaminergic pathways grossly - depigmentation of susbst. nigra and locus coeruleus micro - loss of melanin containing ggl. cells Lewy bodies - intraplasmatic inclusions Other diseases • Huntington d. - fatal disorder of extrapyramidal motor system - chorea+dementia • Amyotrophic lateral sclerosis - (Lou Gehrig-baseball star) - progressive degener. of pyramidal system - muscle weaknes, atrophy • Werding-Hoffmann d. - AR - congenital hypotonia (floppy infant sy) - loss of neurons in anterior horns - death in 1stY • Pick d. - lobar atrophy - less frequent than Alzheimer, similar clinical features Diseases of peripheral nervous system axons of motoric and sensoric neurons, Schwann cells (myelin) two groups of diseases: • peripheral neuropathies • tumors of peripheral nerves Peripheral neuropathies • nutritional and metabolic (DM, avitaminosis B1-thiamine, B6-pyridoxine), alcoholism, renal failure • toxic (lead, arsenic, antitumor drugs-cisplatin, vincristine, organic solvents) • inflammatory (Guillain-Barrι, vasculitic neuropathy, leprosy, sarcoidosis) • hereditary • miscellaneous (amyloidosis, paraneoplastic, Ig disorders) Wallerian degeneration - transection of a nerve - distal to point of transection regeneration - 1mm/day Tumors of peripheral nerves Schwannoma (neurilemmoma, neurinoma) tumor of Schwann cells solitary, encapsulated, sometimes pigmented any peripheral nerve, often N.VIII (acoustic neuromas - deafness) or spinal nerves (paravertebral) nerve at the periphery of the tumor (surgery possible!) Histo - 2 components: Antoni A - organized, palisaded (Verocay bodies) Antoni B - myxoid, patternless no risk of malignant transformation Neurofibroma tumor of Schwann cells - similar nature more frequently multiple, sometimes unencapsulated peripheral branches of nerves - fusiform enlargement - subcutaneous tissue nerve embedded within tumor Histo - loose structure, slender elongated cells with "wavy" nuclei no palisades risk of malignant transformation (Χit is rare!) Neurofibromatosis (von Recklinghausen's disease) inherited - AD - multiple neurofibromas anywhere (skin, retroperitoneum, GIT, spinal nerves) skin lesions (pedunculated neurofibromas, cafι au lait spots) high risk of malignant transformation!!! - malignant peripheral nerve sheath tumor (MPNST) Elephant Man (D. Lynch)