The central nervous system (CNS) is the body’s major communication network. Because of localization of functions, neurologic deficits related to disease processes are variable in their presentation. In certain locations of the brain, a lesion will cause minimal or no symptoms, whereas in other areas, it will cause major neurologic deficits. CNS disease can present in many ways, including changes in consciousness, focal neurologic deficits (e.g., aphasia and amnesia, motor and sensory defects), headaches, dizziness, and seizures. Knowledge of the various neurologic pathways will allow a physician to localize the cause of the patient’s symptoms.

CNS diseases are classified within one of many categories, including vascular diseases (e.g., infarcts and spontaneous hemorrhages), trauma, infections, neoplasms, degenerative diseases, toxic and metabolic disorders, and demyelinating diseases. Because the pathology of nervous system diseases is intimately related to their neurologic manifestations, this chapter will begin with a discussion of clinical presentations of central nervous system disorders. This will be followed by a discussion of basic pathologic changes, malformations, vascular diseases, traumatic disorders, infections of the CNS, neoplasms, degenerative diseases, demyelinating disorders, and, finally, a few basic peripheral nerve and skeletal muscle disorders.

Requirement for consciousness: Intact and functioning brainstem reticular activating system and its cortical projections.

Terminology for impaired levels of consciousness, in order of increasing severity

• Confusion: Impairment of the capacity to think with normal speed and clarity, associated with inattentiveness and disorientation. Delirium is a special example of an acute confusional state in which impaired attention and reasoning are associated with agitation, hallucinations, and in some cases, tremor and convulsions.
  
• Drowsiness: Inability to remain awake without external stimulation; often associated with some degree of confusion.
  
• Stupor: State in which only vigorous external stimulation can arouse the patient; once aroused, responses remain markedly impaired.
  
• Coma: Deep sleep-like state; patient cannot be aroused even with vigorous or repeated external stimulation.

Causes of change in consciousness

1. 
   

   With abnormal CT scan

   
   
   
   
   • Hemispheric mass lesions that cross the midline or impinge upon the brainstem.
     
   • Brainstem lesions that directly affect the reticular formation.
     
   • Subarachnoid hemorrhage.
   
   
   
   
2. 
   

   With normal CT scan

   
   
   
   
   • Inflammatory disorders, such as bacterial meningitis and viral encephalitis.
     
   • Exogenous toxins, such as sedative drugs, alcohols, opioids, and carbon monoxide.
     
   • Endogenous metabolic insults, such as global hypoxic-ischemic insults, hypoglycemia, hyperammonemia, and hypercalcemia.
     
   • Postictal state.
     
   • Selective brainstem ischemia.
   
   

Diagnosis of cause of changes in consciousness: Establishing a differential diagnosis for the cause of a patient’s change in consciousness requires evaluation of the history preceding the change, the physical examination, and the effectiveness of initial empirical therapy.

Categories of cause of changes in consciousness

• Toxic and metabolic (e.g., opiate overdose, alcohol).
  
• Infectious (e.g., meningitis, encephalitis, septic shock).
  
• Cerebrovascular (e.g., stroke).
  
• Trauma.
  
• Other (e.g., seizures, neoplasms).

Role of history in diagnosis of changes in consciousness

• Preceding headache suggests meningitis, subarachnoid hemorrhage, or encephalitis.
  
• Preceding intoxication, confusion, or delirium suggests a diffuse process such as meningitis, endogenous metabolic insults, or exogenous toxins.
  
• Sudden onset of coma suggests brainstem infarct or hemorrhage (e.g., subarachnoid hemorrhage).

Role of physical examination in diagnosis of changes in consciousness

• Localizing signs: Suggest focal lesion.
  
• No localizing signs: Suggests encephalopathy as a result of either an exogenous toxin or an endogenous metabolic insult.

Structural versus Metabolic Causes of Coma

Asymmetrical or reflex functioning of the motor system indicates a focal mass lesion. Changes in pupillary size and reflexes are also useful in assessing the cause of coma.

• A unilaterally dilated nonreactive pupil suggests oculomotor nerve (CN III) compression by an expanding hemispheric mass.
  
• Pinpoint minimally reactive pupils suggests compromise of the pontine tegmentum (e.g., in a pontine hemorrhage); may also be seen in opiate intoxication. Small but reactive pupils are a feature of many metabolic encephalopathies.
  
• Minimally reactive pupils in a mid or slightly dilated position suggests a midbrain lesion.
  
• Bilaterally dilated, nonreactive pupils can be seen in cases of damage to the midbrain tectum or in global ischemic brain injury. It may also be caused by atropine and similar anticholinergic agents.

Overview: Focal lesions within the brain can cause symptoms that help the physician localize the lesion to a specific site. These localizing cortical defects include weakness, visual changes, decreased sensation, and a few specialized conditions such as aphasia and amnesia, and others conditions including agnosia and apraxia. Aphasia and amnesia are described in this section.

Aphasia

Basic description: Aphasia is impairment or loss of language function due to damage to language centers in the dominant hemisphere (usually the left). In addition to the two forms of aphasia (Broca and Wernicke aphasia) described below, there are many other forms, such as conduction aphasias caused by lesions to the arcuate fasciculus and global aphasia.

Broca (expressive) aphasia

Basic description: Disorder of fluency of speech affecting both speech and writing. Patients speak with “broken sentences” but comprehension is intact.

Association: Contralateral arm and face weakness due to the proximity of Broca’s area to the motor cortex.

Area involved to produce Broca aphasia: Dominant hemisphere (usually left), inferior frontal lobe.

Wernicke (receptive) aphasia

Basic description: Impairment of comprehension of written and spoken language. Patient can speak but sentences are meaningless (i.e., “wordy sentences”).

Area involved to produce Wernicke aphasia: Inferior superior temporal cortex of the dominant hemisphere.

Amnesia

Overview: In general terms, amnesia indicates the presence of a memory deficit. With anterograde amnesia, patients cannot form new memories. This type of amnesia commonly occurs after cerebral trauma or with dementia. With retrograde amnesia, patients cannot recall past events. Areas of the brain most commonly affected in patients with amnesia include the hippocampus and the diencephalon (hypothalamus, thalamus). One specific form of amnesia discussed here is Korsakoff syndrome.

Korsakoff syndrome

• Cause: Untreated Wernicke encephalopathy (due to thiamine deficiency); most commonly associated with chronic alcoholism.
  
• Symptoms: Anterograde amnesia, confabulation, ophthalmoplegia, ataxia.

Causes of primary headache: Vascular (e.g., migraine), musculoskeletal, tension headaches, cluster headaches, sinus disease.

Secondary causes of headache: Conditions associated with increased intracranial pressure.

Terminology related to dizziness (dizziness is a nonspecific term)

• Vertigo: Rotational sensation.
  
• Presyncope: Lightheadedness, near fainting, dimming of vision.
  
• Disequilibrium: Dysfunctional balance or gait.
  
• Nystagmus: Involuntary drifting eye movements accompanied by rapid corrective movement. Direction can be horizontal, vertical, rotatory, or mixed. Pure vertical nystagmus is almost always associated with a central lesion.

Forms of vertigo

• Peripheral vertigo: Affecting the inner ear, cochlear apparatus, or vestibulocochlear nerve (CN VIII). Vestibular neuromas are classic but uncommon. In peripheral lesions, the fast phase of nystagmus is away from the affected side.
  
• Central vertigo: Causes include ischemia, hemorrhage, or infarction; occasionally demyelinating diseases or mass lesions.

Basic description of epilepsy: Disease characterized by recurrent paroxysmal electrical discharges in the cerebral cortex known as “seizures.” Manifestations of seizures are variable and include abnormal motor activity, abnormal sensory experiences, and episodic changes in the level of consciousness.

Epidemiology: Seizures can begin at any time during the lifespan; 2–4% of the population has seizures.

Causes of seizures: The incidence of seizures has a bimodal distribution, with seizures in younger patients most often related to epilepsy. The increase in incidence in the elderly population is most often related to cerebrovascular disease and stroke. Most primary seizure disorders are idiopathic and are labeled broadly as epilepsy. Secondary causes of seizures include traumatic brain injury, febrile seizures in children, and tumors.

Absence seizures: Common in children; characterized by staring spells, and classically associated with a 3 Hz “spike and wave” pattern on electroencephalogram (EEG).

Neuronal changes

• Acute changes: “Red” neurons (i.e., neurons with hypereosinophilic cytoplasm and pyknotic nuclei (Figure 11-1); usually caused by ischemic injury.
  
• Subacute and chronic changes: Neuronal loss, inclusions; causes are degenerative diseases.

Astrocytic reactions

• Gliosis: Reactive astrocytes with prominent eosinophilic processes.
  
• Swelling.
  
• Rosenthal fibers: Brightly eosinophilic elongated structures occurring in response to long-standing gliosis as well as several slow-growing tumors.

Microglial reactions: Microglia are cells derived from bone marrow precursors. Accumulations of microglia occur in various patterns, including foam cells in demyelinating disorders and organizing necrosis, and microglial nodules (i.e., compact reactive clusters of microglial cells) in encephalitis.

Overview: Hydrocephalus is dilation of the ventricular system and accumulation of excessive cerebrospinal fluid (CSF). It is most often due to impaired resorption of CSF, and is rarely due to overproduction of CSF.

Forms of hydrocephalus

• The two main forms of hydrocephalus are communicating and noncommunicating hydrocephalus, and the distinction between the two is based upon the location of obstruction to CSF flow (Figure 11-2). Communicating and noncommunicating hydrocephalus and hydrocephalus ex vacuo, which are general conditions due to one of several underlying causes, are discussed in this section. The other two forms of hydrocephalus mentioned below are specific conditions.

Communicating hydrocephalus

• Mechanism: CSF is unable to drain from the subarachnoid granulations into the dural sinuses.
  
• Causes: Include remote meningitis with scarring; chronic subdural hemorrhage.

Noncommunicating (obstructive) hydrocephalus

• Mechanism: An obstruction exists somewhere within the ventricular system.
  
• Causes: Include a tumor in the third ventricle or one that obstructs the foramen of Munro; a tumor of the cerebral aqueduct; or, in infants, a malformed or stenotic aqueduct.

Hydrocephalus ex vacuo

• Mechanism: A compensatory dilation of the ventricles in response to a loss of cerebral parenchyma. Not typically associated with increased intracranial pressure.
  
• Causes: Include Alzheimer disease or a stroke.

Normal pressure hydrocephalus: Patients have dilated cerebral ventricles associated with a normal intracranial pressure. Normal pressure hydrocephalus causes dementia.

Pseudotumor cerebri: Classically seen in young obese females; presents as severe headache with papilledema and elevated intracranial pressure.

Overview: Because of the rigid nature of the cranial vault and dural reflections, the brain has only a limited space in which to expand. Expansion of the brain is associated with a variety of mechanical deformations, including flattening of the gyri (Figure 11-3) and several types of herniation patterns. Although cerebral edema can be a generalized process, expansion of the brain can occur as a local process due to a wide variety of causes, including neoplasms and hemorrhage.

Types of Cerebral Edema

Overview: The two types of cerebral edema are vasogenic and cytotoxic edema, both of which are explained below. However, in many clinical situations, edema is caused by both cytotoxic and vasogenic mechanisms.

1. 
   

   Vasogenic edema

   
   
   
   
   • Basic description: Edema occurring as a result of disruption of the integrity of the blood-brain barrier, allowing fluid to escape into the interstitial tissue. The brain has no lymphatics.
     
   • Examples: Neoplasms, abscesses, infarcts.
   
   
   
   
2. 
   

   Cytotoxic edema

   
   
   
   
   • Basic description: Increase in intracellular fluid due to cellular injury.
     
   • Examples: Generalized ischemic injury, infarcts.
   
   

Complications of cerebral edema

• Cerebellar tonsillar herniation (Figure 11-4): Cerebellar tonsils herniate down the foramen magnum and press on the brainstem. A cerebellar tonsillar herniation is almost always associated with damage to adjacent brainstem structures that control respiration and heart beat, and for that reason, this type of herniation is associated with a high mortality rate.
  
• Uncal (transtentorial) herniation (see Figure 11-4): The uncus (on the medial aspect of the temporal lobe) herniates under the tentorium cerebelli. The uncus can compress the oculomotor nerve (CN III), compromising the parasympathetic fibers and resulting in ipsilateral pupillary dilation with associated ophthalmoplegia (“down and out”). The uncus can also compress the posterior cerebral artery, causing an ipsilateral occipital lobe infarct (Figure 11-5). Cheyne-Stokes respirations are commonly seen with mesial temporal transtentorial herniation.
  
• Cingulate (subfalcine) herniation: The cingulate gyrus herniates under the falx cerebri. The anterior cerebral artery may be compressed, causing an infarct of the frontal or parietal lobe in the midline.
  
• Transcalvarial herniation: When cerebral edema develops in a patient after surgery or trauma, the brain can herniate through the surgical defect in the skull.

Associated condition: Secondary brainstem (Duret) hemorrhage.

• Mechanism of formation of Duret hemorrhage: Kinking of branches of the basilar artery during downward displacement of the brainstem.
  
• Gross morphology: Midline and paramedian streak-like hemorrhage in the brainstem, oriented dorsal to ventral (Figure 11-6).

Overview: Most CNS malformations are classified in one of several categories, including neural tube defects, malformations associated with hydrocephalus (Chiari types I and II), disorders of forebrain development, and disorders of neuronal migration. Each of these categories will be discussed below, with examples of each.

Neural Tube Defects

Risk factors: Include maternal folate deficiency, incompletely defined geographic and other environmental factors, and gender (incidence is greater in females than in males).

Laboratory testing: Increased level of α-fetoprotein.

Examples of neural tube defects: anencephaly and spina bifida

Anencephaly (Figure 11-7)

Mechanism of formation: Failure of closure of the anterior neuropore.

Manifestation: Failure of development of the brain and the calvarium.

Incidence: 2–3 in 1000 live births.

Spina bifida

Mechanism of formation: The more severe forms of spina bifida are the result of failure of closure of the posterior neuropore. Less severe forms, such as spina bifida occulta, are the result of failure of secondary neurulation and failure of tail bud formation.

Manifestation: Varies from spina bifida occulta (i.e., incomplete vertebral arch) to myelomeningocele, which has prolapse of the meninges and spinal cord through the defect in the vertebral arch. The most common finding in spina bifida occulta is an abnormal growth of hair over the affected vertebral segment.

Symptoms of spina bifida: Some patients are asymptomatic, whereas other patients have motor and sensory dysfunction and poor bowel and bladder control. The symptoms manifested depend upon the severity of the defect.

Malformations Associated with Hydrocephalus (Chiari Types I and II)

Chiari type I malformation

Gross morphology: Herniation of elongated segment of the inferior cerebellar vermis and paravermal folia through the foramen magnum.

Complications: Many patients are asymptomatic; however, the lesion is associated with cranial nerve abnormalities, sudden death, and, in adults, with cerebellar ataxia and late-onset hydrocephalus. Approximately 90% of cases of idiopathic syringomyelia (an abnormal cavity in the spinal cord) have an associated Chiari type I malformation.

Chiari type II malformation

Gross morphology: Abnormally shallow posterior cranial fossa associated with a caudal “herniation” of the medulla and portions of the cerebellar vermis through the foramen magnum.

Complications: Hydrocephalus.

Important point: Almost all cases of Chiari type II malformations are associated with a meningomyelocele in the lumbosacral spinal cord.

Disorders of Forebrain Development

Overview: Disorders of forebrain development include holoprosencephaly, agenesis of corpus callosum, and absence of septum pellucidum. Only holoprosencephaly will be discussed here.

Holoprosencephaly

Basic description: Malformation resulting from abnormal growth and separation of the developing forebrain.

Incidence: 1 in 30,000 births. Most cases are sporadic, but familial forms also occur.

Risk factors: Certain maternal and environmental factors (e.g., maternal diabetes mellitus, fetal alcohol syndrome, congenital infections), trisomy 13, and mutations in the ZIC2 gene on chromosome 13q. Other cases of holoprosencephaly have been mapped to several additional genetic loci.

Morphology of three types of holoprosencephaly

• Alobar holoprosencephaly: The brain has no hemispheric development. A rudimentary forebrain overlies a common ventricular cavity. The straight gyri, olfactory structures, and commissural structures (e.g., corpus callosum) are absent. There are also severe facial abnormalities (e.g., cyclopia).
  
• Semilobar holoprosencephaly: Some development of an interhemispheric fissure; straight gyri, olfactory structures, and corpus callosum usually are still absent.
  
• Lobar holoprosencephaly: Interhemispheric fissure is present, and individual lobes are distinguishable; however, there is some continuity of the cerebral cortex in the midline and aplasia or dysplasia of the corpus callosum.

Disorders of Neuronal Migration

• Agyria (lissencephaly): The brain is virtually devoid of surface convolutions expected for age.
  
• Pachygyria: Reduced numbers of gyri, and gyri present are abnormally broad.
  
• Polymicrogyria: Numerous abnormally convoluted gyri.
  
• Other disorders of neuronal migration: Neuronal heterotopias, white matter heterotopias.

Overview: Primary malformations may be difficult to distinguish from acquired injury, because prior to 16 weeks’ gestational age, the brain does not mount the usual reaction to injuries. Germinal matrix hemorrhage, periventricular leukomalacia, porencephaly, and multicystic encephalopathy are discussed in this section.

Germinal matrix hemorrhage: Hemorrhage occurring in premature infants (see Chapter 7).

Periventricular leukomalacia (PVL)

• Morphology: Chalky discoloration of the white matter associated with hemorrhage and cavitation.
  
• Risk factors: Hyaline membrane disease, shock, sepsis, and congenital heart disease.
  
• Important point: PVL is often seen in association with cerebral palsy.

Porencephaly: Cystic defect with a smooth contour that allows the ventricular system to communicate with the subarachnoid space (Figure 11-8). Most examples likely represent sequelae of intrauterine ischemic injury early in gestation.

Multicystic encephalopathy: Irregularly distributed cystic lesions that lack a smooth contour. Lesions develop due to injury later in gestation than injury that causes porencephalic defects.

Arteriovenous malformation

• Morphology: Mass of enlarged arteries, veins, and hybrid channels, with intervening nervous tissue.
  
• Epidemiology: 10–30 years of age; male predominance.
  
• Location: Most occur along the distribution of the middle cerebral artery.
  
• Complications of arteriovenous malformation: Seizure disorder, intracerebral hemorrhage, subarachnoid hemorrhage.

Cavernous angioma: Dilated venous spaces (no arterial component) with no intervening nervous tissue; these malformations may bleed.

Capillary angioma: Proliferation of small diameter blood vessels; most are asymptomatic.

Overview: Cerebrovascular disease is the third main cause of death in adults. The most common causes are thrombosis, emboli, and hemorrhage. Cerebrovascular disease can be generalized, as might be seen following cardiac arrest (global hypoxic ischemic encephalopathy), or it can be localized (cerebral infarct). The term “stroke” is used to designate the sudden onset of a localized, nonconvulsive, neurologic deficit. Strokes can be caused by either a cerebral infarct or a primary (nontraumatic) hemorrhage. Stroke, global hypoxic-ischemic encephalopathy, cerebral infarcts, and intracerebral hemorrhage will be discussed in this section.

Stroke

Basic description of stroke: Term used when CNS symptoms begin suddenly and persist for more than 24 hours. As noted, strokes can be caused by ischemic injury or by primary hemorrhage; 80% are ischemic in origin.

Basic description of transient ischemic attack (TIA): Brief episode of neurologic dysfunction relating to a specific vascular bed that lasts less than 24 hours. TIAs are usually caused by small emboli. The risk of having a future stroke following a TIA is 15% within 1 year and 25% within 2 years.

Clinical presentation of stroke: Acute spontaneous onset of central, localizing, neurologic dysfunction of more than 24 hours’ duration.

Global Hypoxic-Ischemic Encephalopathy

Basic description: Condition resulting from generalized poor perfusion of the brain, and hence is probably more properly termed “ischemic” encephalopathy. Some areas of the brain are more sensitive than others.

Cause: Global cerebral ischemia.

Areas most commonly affected by global hypoxic-ischemic encephalopathy in adults

• Arterial borderzone areas (i.e., regions between the distribution of the cerebral arteries).
  
• Hippocampus (particularly the so-called CA1 region of the pyramidal cell layer).
  
• Purkinje cells and dentate nucleus in cerebellum.
  
• The basal ganglia and thalamus are other common sites of injury.

Morphology of global hypoxic-ischemic encephalopathy

• Gross: Appearance depends upon time period since injury; can have edema, dusky red discoloration (particularly if there has been reperfusion), and laminar cortical necrosis (midcortical layer neurons are most susceptible to ischemic injury). In the cerebral cortex, ischemic injury is almost always more pronounced at the depths of sulci than in the gyral crests.
  
• Microscopic: At 12–24 hours, “red” neurons (i.e., neurons with eosinophilic cytoplasm and pyknotic nuclei). There is usually minimal host inflammatory reaction due to lack of perfusion of the brain.

Cerebral Infarcts

Basic description: Focal irreversible brain injury resulting from a localized loss of blood flow.

Causes of cerebral infarcts

• In the anterior circulation, most commonly middle cerebral artery territory, infarcts are usually due to emboli from atherosclerotic plaques in the carotid arteries.
  
• In the posterior circulation, infarcts are usually from thrombi due to atherosclerosis. Vasculitis (either infectious or noninfectious) and trauma are less common causes.

Types of cerebral infarcts

• Hemorrhagic infarct: Causes are usually emboli or conditions associated with compression of the vessels such as herniations.
  
• Nonhemorrhagic infarct: Cause is usually thrombi.

Three stages of morphologic development of a cerebral infarct (Table 11-1)

• Acute.
  
• Organizing (changes develop beginning about day 3).
  
• Remote (changes develop within 6 months after infarct).

Morphology of acute infarcts

• Gross: Soft parenchyma with preservation of architecture. Hemorrhagic infarcts have petechial hemorrhages and larger hemorrhages as a result of reperfusion (Figure 11-9).
  
• Microscopic: Red neurons and rarefaction of white matter (within 12–24 hours) are associated with a neutrophilic infiltrate. In hemorrhagic infarcts, there are extravasated red blood cells as a result of reperfusion.

Morphology of organizing infarcts

• Gross: Soft, friable parenchyma with loss of architecture; the lesion becomes more sharply defined over time (Figure 11-10).
  
• Microscopic: Foamy macrophages containing engulfed myelin debris begin to infiltrate within 48–72 hours and remain in the area for about 6 months (Figures 11-11, 11-12, 11-13).

Morphology of remote infarcts

• Gross: Cystic lesion (Figure 11-14).
  
• Microscopic: Gliosis. If the infarct is near the cortical surface, there is subpial sparing because the subpial parenchyma receives its oxygen and nutrients from the CSF and meningeal vessels.

Clinical presentation of infarcts: Symptoms depend upon the size and location of the infarct.

• Middle cerebral artery distribution: Contralateral hemiparesis and hemisensory loss; the face and upper extremity are more affected than the lower extremity; aphasia if the infarct involves the dominant cerebral hemisphere.
  
• Anterior cerebral artery distribution: Contralateral hemiparesis and hemisensory loss; the lower extremity is more affected than the upper extremity.
  
• Posterior cerebral artery distribution: Contralateral hemiparesis, homonymous hemianopsia, amnesia, sensory loss.
  
• Basilar artery distribution: Quadriparesis, dysarthria, dysphagia, diplopia.