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Neuroanatomy

Note: Significant diseases are indicated in bold and syndromes in italics.

I. Cerebral Cortex

1.Important gyri, lobes, and Brodmann areas (Fig. 1–1)

2.Types of cortical neurons (Fig. 1–2)

a.projection neurons: pyramidal and fusiform neurons

b.interneurons: stellate and granule cells, horizontal cells of Cajal

3.Chemoanatomy

a.afferents

i.corticocortical fibers and thalamocortical fibers (glutamate, aspartate)

ii.projections from the nucleus basalis of Meynert (acetylcholine), hypothalamus (histamine, orexin/hypocretin), and brainstem (norepinephrine, serotonin, dopamine)

b.efferents

i.all use glutamate and aspartate

4.Subtypes of cortex

a.cytoarchitectonic subtypes

i.isocortex: exhibits the six typical layers

(1)homotypical isocortex: the six layers are proportionate

(2)heterotypical isocortex: certain layers are enlarged, for example, the

(a)primary motor cortex (Brodmann area 4) exhibits an enlarged layer 5 due to oversized pyramidal cells that project into the corticospinal tract {Betz cells}

A B

Cerebral Cortex

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A B

Figure 1–3 Sensory (A) and motor (B) homunculi. Note the proximity of the thumb to the forehead. (From Duus P, Topical Diagnosis in Neurology. Stuttgart, Germany: Georg Thieme; 1998:273, Fig. 8.20. Reprinted by permission.)

(1)global akinesia with speech arrest that develops into hypokinesia (contralateral ipsilateral), reduced speech, and reduced facial expression; chronically, patients will exhibit only poor hand coordination

(2)ideomotor apraxia, which may be associated with a contralateral alien hand phenomenon characterized by unconscious reflexive movements

ii.stimulation causes bilateral posturing movements, contralateral head and body rotation, and vocalizations {salutary seizures}

3.Subcortical projections

a.corticobulbar tract: the ventral division travels with the corticospinal tract and synapses in the facial nucleus; the dorsal division travels closer to the medial lemniscus and synapses in other cranial nerve nuclei and the reticular formation

b.corticospinal tract: composed of fibers not only from the primary motor cortex (25%) and monomodal motor association cortex (30%) but also the primary somatosensory cortex (30%) and superior parietal lobule (Brodmann areas 5 and 7; 15%)

i.terminates in the cervical spinal cord (55%), thoracic spinal cord (20%), and lumbosacral spinal cord (25%)

ii.the majority (80%) of the corticospinal tract decussates at cervicomedullary junction (upper extremity fibers decussate rostral to the lower extremity fibers)

(1)the rest of the corticospinal tract does not decussate until it arrives at its terminal cervical and upper thoracic spinal cord levels (ventral corticospinal tract)

B.Somatosensory Systems

1.Primary sensory cortex (Brodmann areas 3-1-2) a. subdivided according to sensory modality

i.Brodmann area 3a receives deep sensation from muscle spindles and Golgi tendon organs

ii.Brodmann area 3b receives superficial sensation from exteroceptors and cutaneous receptors

Cerebral Cortex

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iii.Brodmann areas 1 and 2 receive deep and superficial sensation including subcutaneous tissues

b.somatotopic organization: similar to the motor homunculus, but less well defined and may extend caudally into Brodmann areas 5 and 7

i.face and body are bilaterally represented; limbs are unilaterally represented

c.lesions cause loss of proprioception (but not vibration sensation), poor localization of stimuli {topagnosia}, difficulty with two-point discrimination, reduced object recognition through touch {astereognosis}, tactile hallucinations, rapid fatigability of prolonged sensory stimulation, and paresthesias

i.primary modality sensory loss is pronounced with postcentral gyrus lesions that involve the posterior insula and underlying white matter

d.stimulation produces numbness and paresthesias, and often a sensation of movement

2.Secondary sensory cortex (supramarginal gyrus; Brodmann area 40): Posterior to the inferior part of the primary somatosensory cortex

a.exhibits bilateral inputs with contralateral predominance, and is somatotopically organized into a separate homunculus that may be related to pain sensation

3.Unimodal somatosensory association area (Brodmann area 5): Involved in recognition of object shape by tactile sensation {stereognosis}

4.Subcortical afferents: anterolateral system/spinothalamic tract, dorsal columns, and trigeminal pathways terminate in the ventroposteromedial and ventroposterolateral thalamic nuclei that then project to the primary sensory cortex

C. Special Sensory Systems

1.Vision (see p. 37) and hearing (see p. 48)

2.Vestibular sensation (see p. 50)

3.Taste (Brodmann area 43): Adjacent to the primary somatosensory tongue representation and the insular cortex motor areas for salivation and gastrointestinal motility

a.distorted taste perception {dysgeusia} is poorly localized and usually is caused by zinc or vitamin A deficiency

4.Olfaction: represented by bilateral projections from the olfactory nerves to the piriform cortex and amygdala via lateral olfactory stria, and to the orbitofrontal cortex overlying the septal nuclei via the medial olfactory stria; no olfactory bulb projections enter the anterior perforated substance in humans

a.distorted odor perception {parosmia} is usually caused by injury to the olfactory nerves from head trauma or by psychiatric illness (e.g., depression)

b.olfactory hallucinations can be caused either by injury to the olfactory nerves or by seizures in the mesial temporal lobe or uncus that involve the amygdala (Box 1.1)

D. Heteromodal Association Areas

1.Frontal heteromodal association area/prefrontal cortex: involves all the cortex located anterior to the monomodal motor association areas

a. unlike other heteromodal association areas, the prefrontal cortex

i.projects to the amygdala and caudate

ii.receives indirect projections from the hippocampus through the dorsomedial thalamus and direct projections from the cingulate gyrus

Box 1.1

Other Types of Hallucinations

Visual—Formed hallucinations from posterior temporal lobe or mesencephalon (i.e., peduncular hallucinosis) dysfunction or in reaction to vision loss {Bonnet’s syndrome}, which have hallucinations in the area of vision loss; unformed hallucinations with occipital lobe dysfunction

Auditory—Formed hallucinations from superior temporal gyrus dysfunction; unformed hallucinations from pontine dysfunction, usually in the presence of hearing loss

Gustatory—from frontoparietal cortex dysfunction

Table 1–1 Frontal Lobe Syndromes

b.lesions: in addition to the injured part of the prefrontal cortex, the depth of the lesion and the age at which the patient was injured will also affect the symptoms (Table 1–1)

i.Bruns’ frontal lobe ataxia/marché à petits pas of Dejerine—wide-based, slow, short-stepped gait with flexed posture and frequent freezes; can progress to inability to stand

(1)caused by lesions anywhere in frontal lobes that are often bilateral and multifocal

2.Parietal heteromodal association areas: Located in the superior and inferior parietal lobules

a.dominant-sided lesions produce (Box 1.2)

i.alexia

ii.Gerstmann’s syndrome—classically involves agraphia, finger agnosia, acalculia, and left-right confusion; lesions are located on the angular gyrus (Brodmann area 39)

iii.contralateral tactile neglect and spatial inattention

iv.somatotopic ideomotor apraxia

b.nondominant-sided lesions produce

i.contralateral tactile neglect and spatial inattention, which may be so severe that the patient does not recognize the deficit {anosognosia}

ii.constructional and dressing apraxias

iii.spatial disorientation

iv.impersistence; inattention; static confusional state/encephalopathy

E. Language Areas

1.Dominant hemisphere language areas

a.Broca’s area: located in the inferior frontal gyrus, and includes the pars opercularis (Brodmann area 44; a monomodal motor association area) (Box 1.3) and the pars triangularis (Brodmann area 45; a heteromodal association area)

i.lesions produce

(1)Broca’s aphasia—classically involves Broca’s area, the mouth representations of the primary motor and somatosensory cortices, and the underlying white matter

(a)symptoms include nonfluent speech that is slow and agrammatic as well as dysarthric, and impaired repetition; writing is minimal and agrammatic

Cerebral Cortex

Box 1.2

Large dominant-sided inferior parietal lobule lesions can cause an acquired illiteracy.

Box 1.3

Bilateral damage of Brodmann area 44 that extends into the inferior parietal lobe causes loss of voluntary eye, face, oropharynx, and tongue movements (an apraxia).

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(2)aphemia—a pure anarthria caused by lesions strictly limited to Broca’s area (i.e., not involving the primary motor and somatosensory cortices or the underlying white matter); may also be caused by bilateral lesions of the corticobulbar tracts

b.Wernicke’s area

i.includes posterior superior and middle temporal gyri, planum temporale (Brodmann area 42; a monomodal auditory association area), and heteromodal association areas of the parietal lobe (angular and supramarginal gyri; Brodmann areas 39 and 40)

ii.lesions cause Wernicke’s aphasia

(1)characterized by excessive speech of normal cadence and prosody associated with impaired naming, comprehension, and repetition, and the presence of paraphasias and neologisms; writing is similarly excessive with paraphasias and neologisms

(2)impairment of comprehension can be particularly pronounced with specific subjects, thereby giving the false appearance of a fluctuant deficit

c.secondary language areas (i.e., the cortex surrounding Broca’s and Wernicke’s areas): lesions produce the transcortical aphasias because they isolate the primary language areas without directly injuring them; all have preservation of repetition

i.subtypes of transcortical aphasias

(1)transcortical motor aphasia—generally caused by lesions anterior or superior to Broca’s area, or by lesions in the supplementary motor area

(2)transcortical sensory aphasia—can be caused by lesions surrounding Wernicke’s area, but otherwise is usually poorly localized

(3)mixed transcortical aphasia—caused by large areas of dominant hemisphere injury that spare the perisylvian regions (e.g., as in watershed infarction or dementias)

d.subcortical connections of Broca’s and Wernicke’s areas: lesions produce

i.conduction aphasia—caused by disconnection of Broca’s and Wernicke’s areas, most commonly the result of a subcortical white matter lesion that interrupts the arcuate fasciculus (in the superior longitudinal fasciculus; and/or the extreme capsule

(1)symptoms: isolated loss of repetition with occasional paraphasic errors

ii.anomia—generally has no localizing value when mild, but significant anomia may reflect lesions in the basal temporal lobe that interrupt hippocampal projections to Wernicke’s area

2.Nondominant hemisphere language areas

a.areas related to the variation of pitch, intonation, melody, rhythm, and loudness of speech {prosody}

i.affective prosody—involves the expression of mood and emotion in speech; caused by lesions in the nondominant hemisphere in areas that are anatomical and functional parallels to Broca’s and Wernicke’s areas of the dominant hemisphere

(1)affective prosody is most commonly observed in psychiatric diseases (e.g., motor and sensory aprosodies in schizophrenia, motor hyperprosody in mania)

ii.propositional prosody—defines a phrase as a question or a statement; can occur after lesions of either hemisphere

b.areas related to gesturing that accompanies speech {kinesia}: poorly localized

c.areas related to singing: an acquired inability to sing {amelodia} is caused by lesions of the posterior inferior frontal lobe or anterior parietal lobe

Cerebral Cortex

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b.functions

i.olfactory sensory processing and integration of olfactory-visceral reflexes

ii.coordination of emotional behavior and autonomic nervous system responses

iii.association of memories with their emotional content

c.lesions generally produce a loss of aggressive behavior; stimulation produces fear or defense reactions

II. Subcortical White Matter

1.Corona radiata/Centrum semiovale

a.pathophysiology

i.leukoaraiosis: can be part of, but is not identical to, vascular dementia or Binswanger’s disease

(1)lesion types include (Fig. 1–6)

(a)irregular white matter abnormalities, typically scattered about randomly

(i)histology: resembles ischemia

(b)periventricular white matter caps and halos

(i)histology: resembles demyelination (not ischemia), with subependymal gliosis and breakdown of the underlying ependyma of the ventricles

b.internal capsule (Fig. 1–7)

i.pathophysiology: the striatocapsular syndrome, typically caused by infarction from occlusion of a lenticulostriate artery; symptoms include

(1)hemiparesis (95%), which is often the only symptom {pure motor syndrome} (Box 1.5)

(2)hemi-sensory loss (60%)

(3)aphasia or neglect (60%)

c.association fibers

i.short association fibers/“U” fibers: short-range cortical–cortical projections

ii.long association fibers (Fig. 1–8)

(1)cingulum: connects the temporal and prefrontal heteromodal cortices with the cingulate gyrus

(2)uncinate fasciculus: connects the temporal and prefrontal heteromodal cortices

Figure 1–6 Leukoaraiosis. (From Hosten N, Liebig T, CT of the Head and Spine. Stuttgart, Germany: Georg Thieme; 2002:31, Fig. 1.33b. Reprinted by permission.)

Box 1.5

Differentiate striatocapsular syndrome from primary motor cortex lesions that may allow reflex movements of the apparently paralyzed limb (mediated by monomodal motor association areas).

Subcortical White Matter

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(3)superior longitudinal fasciculus: connects the parietal and temporal lobes with the frontal lobe; includes the arcuate fasciculus, lesions of which cause conduction aphasia

(4)inferior longitudinal fasciculus: connects the occipital cortex with the inferior temporal and fusiform gyri; important for the ventral occipitotemporal neural network, which is involved in face and object recognition (the “what” pathway)

(5)superior occipitofrontal fasciculus: interconnects all the lobes; important for the dorsal parietofrontal neural network, which is involved in spatial orientation (the “where” pathway)

(6)inferior occipitofrontal fasciculus: connects the inferior temporal, fusiform, and lingual gyri with the frontal lobe

d. commissures

i.corpus callosum: regions of the cortex project through the corpus callosum to symmetric regions in the contralateral hemisphere, and occasionally to other regions; fibers originate from cortex layer 3

(1)pathophysiology

(a)transection of the corpus callosum: symptoms are generally detectable only by specific testing, and include

(i)inability to name objects or read words presented in the visual hemifield of the nondominant hemisphere

(ii)inability to name objects felt by the nondominant hand

(iii)inability to write with the nondominant hand

(iv)impaired spatial construction skills with the dominant hand

(v)callosal alien hand syndrome—discoordination of simultaneous voluntary hand movements

ii.anterior commissure: connects the caudal orbitofrontal, anterior temporal, and parahippocampal cortices as well as the contralateral olfactory nerve to the piriform cortex for bilateral olfactory representation

iii.posterior commissure: carries fibers of the medial longitudinal fasciculus, posterior thalamus, pretectal nuclei, mesencephalic accessory ocular motor nuclei, and superior colliculi

iv.hippocampal commissure: minimal size and function in humans

Putamen

Extreme capsule

underneath Superior the insula temporal

gyrus

Claustrum

Septum pellucidum above the fornices

Figure 1–9 The basal forebrain posterior to the nucleus accumbens demonstrating the olfactory cortex, septal nuclei, and ventral basal ganglia (inferior to the anterior commissure). (From Kahle W, Color Atlas/Text of Human Anatomy, Vol. 3: Nervous System and Sensory Organs. 4th ed. Stuttgart, Germany: Georg Thieme; 1993:201, Fig. B; 211. Reprinted by permission.)

III. Basal Forebrain (Fig. 1–9)

1.Septal region: Includes

a.septal nuclei: the lateral septal nucleus receives input from the medial olfactory stria, the hypothalamus, and the hippocampus via the fimbria-fornix, and relays that information to the medial septal nucleus; projections from the medial nucleus (acetylcholinergic as well as GABAergic) go to the hippocampus via the fornix and to the brainstem via the medial forebrain bundle

b.nucleus of the diagonal band of Broca, which provides acetylcholinergic innervation to the hippocampus as do the septal nuclei

c.nucleus accumbens: the equivalent of the caudate and putamen for a limbic basal ganglia loop (Table 1–2); receives dopaminergic afferents from the ventral tegmental area and is involved in positive reinforcement and craving behaviors

d.islets of Calleja, which have a poorly defined function

2.Nucleus basalis of Meynert: Similar to the septal nuclei but provides acetylcholinergic innervation to the cortex (particularly pronounced in limbic and paralimbic areas) and extrinsic cholinergic innervation to the striatum (although 80% of striatal acetylcholine is intrinsic) and not to the hippocampus; functions in memory formation and retrieval

IV. Basal Ganglia (Fig. 1–10)

1.Striatum: Includes the caudate, putamen, and nucleus accumbens; some also include the claustrum

a.neuron types: the motor striatum (caudate and putamen) and the limbic striatum (nucleus accumbens) are cytologically identical

i.spiny neurons: project from the striatum to the globus pallidus and substantia nigra

(1)nondopaminergic inputs to the spiny neurons terminate on the tips of their spines; dopaminergic inputs terminate on the spine bases, thereby modulating the efficiency of the nondopaminergic inputs

Basal Ganglia

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Thalamus

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To cingulate gyrus

Anterior ventral and

Figure 1–12 Functional divisions of the thalamus. (From Duus P, Topical Diagnosis in Neurology. Stuttgart, Germany: Georg Thieme; 1998:275, Fig. 8.22. Reprinted by permission.)

(i)hemiataxia, usually with hemiparesis and/or sensory loss from involvement of nearby structures; develops acutely after injury

(ii)intention tremor: develops several weeks after injury

(iii)dystonia: develops several months or years after injury

(3)lateral geniculate (see p. 14) (Box 1.9)

(4)medial geniculate

(5)ventral posterior nuclei

(a)ventral posterolateral nucleus has distinct areas for proprioception (i.e., the shell of the nucleus) and cutaneous (i.e., the core) inputs from body

(b)ventral posteromedial nucleus receives trigeminal inputs for facial sensation and inputs from the solitary tract nucleus via the solitary tract conveying taste

(c)lesions cause

(i)chiro-oral syndrome—symptoms include the contralateral loss of all sensory modalities and paresthesias of the mouth, tongue, and hand

1.face, trunk, and proximal extremities are bilaterally represented (with a contralateral preference) in the ventral posterior thalamus, and so their sensation is preserved in unilateral lesions

Box 1.9

Lateral geniculate, medial geniculate, and posterior lateral nuclei: sensory nuclei of the ventral nuclei group

Thalamus

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A

Figure 1–14 The hypothalamus in sagittal (A) and coronal (B) views. Panel A shows only the medial hypothalamus. Arrows in panel A correspond to the cross-sections in panel B. (From Duus P, Topical Diagnosis

B

in Neurology. Stuttgart, Germany: Georg Thieme; 1998:194, Fig. 5.13; 195, Fig.5.14. Reprinted by permission.)

1.General functions

a.controls the autonomic nervous system and the endocrine system (Box 1.12)

b.maintains visceral activity, metabolic activity, and body temperature

c.participates in goal-directed behavior and motivation, affective behavior (particularly aggressive behaviors), and sleep–wake cycling

2.Subdivisions (Fig. 1–14)

a.lateral hypothalamus: a “reward” center that likely mediates pleasurable sensations; regulates thirst (by means of vasopressin secretion from the paraventricular and supraoptic nuclei of the supraoptic region) and hunger and food-motivated behaviors (Table 1–3)

b.medial hypothalamus: divided into

i.preoptic region

(1)median preoptic nucleus: a sexually dimorphic nucleus

Table 1–3 Neurogenic Syndromes of Water Imbalance

Box 1.12

Autonomic Effects of Stimulation

Parasympathetic effects: Preoptic region (medial hypothalamus), supraoptic region (medial hypothalamus)

Sympathetic effects: Mammillary region (medial hypothalamus), lateral hypothalamus

(2)medial preoptic nucleus: regulates body temperature and febrile responses (Box 1.13)

(3)lateral preoptic nucleus: promotes sleep onset, and inhibits brain regions that are necessary for maintaining arousal by GABAergic and galanin projections

ii.supraoptic region

(1)neurohormonal/magnocellular nuclei (paraventricular and supraoptic nuclei): project to the posterior pituitary where they directly release hormones

(2)suprachiasmatic nucleus: the pacemaker of circadian rhythms (e.g., sleep–wake cycle, body temperature, cortisol and growth hormone release)

(a)receives direct input from the retina; projects predominantly to the preoptic region and neurohormonal nuclei

(b)lesions cause irregular timing of sleep–wake behaviors; otherwise a normal amount of time is spent in each sleep phase

iii.tuberal region

(1)ventromedial nucleus: inhibits feeding behaviors together with the arcuate nucleus; opposed by the lateral hypothalamus (Box 1.14)

(2)hormonal/parvocellular nuclei, which includes the ventromedial and arcuate nuclei: project to the median eminence where they release hormones into the portal system that then influence anterior pituitary hormone release (Table 1–4)

(3)dorsomedial nucleus, tuberal nucleus

iv.mammillary region

(1)mammillary bodies: receives projections from the hippocampus via the postcommissural fornix

(a)serves in the circuit of Papez for memory formation; one of the chief sites of atrophy in Wernicke–Korsakoff syndrome

(2)posterior nucleus: a “punishment” center that likely mediates negative affect; also involved in

(a)inducing and maintaining wakefulness by diffuse histamine projections

(b)initiating rage and fighting behaviors

(c)regulation of the sympathetic nervous system

Table 1–4 Hypothalamic and Anterior Pituitary Hormones

Box 1.13

Responses involved in body temperature regulation include:

Heat loss (preoptic region): vasodilation; sweating, panting; decreased metabolism

Heat production (posterior nucleus): vasoconstriction; shivering, piloerection; increased metabolism

Box 1.14

Froehlich’s Syndrome

Symptoms—Obesity, failure of sexual development, and polyuria, occurring mostly in boys

Cause—Hypothalamic lesions producing multiple releasing hormone deficiencies

Differential diagnosis—Prader–Willi syndrome

Hypothalamus

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Cerebellum

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Simple lobule

Superior semilunar lobule

A

B

Figure 1–17 Dorsal (A) and ventral (B) views of the cerebellum. (From Duus P, Topical Diagnosis in Neurology. Stuttgart, Germany: Georg Thieme; 1998:165, Figs. 4.1, 4.2. Reprinted by permission.)

b.caudal vermis syndrome—symptoms include gait ataxia without limb ataxia, axial disequilibrium, nystagmus, and a rotated head posture

i.typical cause: midline tumors, posterior fossa surgery

c.hemispheric syndrome—symptoms include ipsilateral limb ataxia and dysarthria; does not have nystagmus, but may have ocular dysmetria

i.typical cause: infarction

d.pancerebellar syndrome—symptoms include bilateral symptoms of the other three types of cerebellar syndromes

i.typical cause: infection, paraneoplastic syndromes

8.Pathophysiology: the uncommon cerebellar syndromes

a.symptoms include an oropharyngeal apraxia causing dysphagia, mutism, and an inability to open the eyes; also may exhibit urinary retention

i.typical cause: surgical removal of midline cerebellar tumors

(1)typically develops 1–3 days after surgery

(2)symptoms generally improve but may leave residual dysarthria

b.cerebellar fits/diencephalic autonomic seizures—symptoms include transient decerebrate rigidity occurring most commonly in comatose patients with intracranial mass lesions located in the posterior fossa; often are mistaken for seizures

i.typical cause: transient episodes of increased intracranial pressure, which likely cause periods of mesencephalic dysfunction

c.cerebellar cognitive-affective syndrome—symptoms include slowed decision making, personality changes (disinhibited or blunted), and impaired spatial and language abilities

A

B

Figure 1–18 Vascular anatomy of the cerebellum. (A) Midline view; (B) Inferior view. (From Duus P, Topical Diagnosis in Neurology. Stuttgart, Germany: Georg Thieme; 1998:173, Figs. 4.8, 4.9. Reprinted by permission.)

VIII. Brainstem

A. Mesencephalon

1.Motor output centers

a.eye movements: oculomotor nucleus, trochlear nucleus

b.red nucleus

i.has connections with (Box 1.16)

(1)motor cortices

(2)cerebellar deep nuclei: dentate nucleus (parvocellular red nucleus); interposed nuclei (magnocellular red nucleus)

(3)inferior olivary complex

(4)spinal cord

ii.pathophysiology: palatal myoclonus

(1)classically develops several months after lesions of the central tegmental tract, although 25% of cases are idiopathic; lesions elsewhere in the triangle of Mollaret (Box 1.17) just cause intention tremor

Box 1.16

Cerebellar Peduncles

Superior cerebellar peduncle/brachium conjunctivum:

Afferents from the ventral spinocerebellar tract, red nucleus, tectum, and modulatory inputs

Efferents to the red nucleus (from interposed nuclei) and thalamus (from dentate nucleus)

Middle cerebellar peduncle: Exclusively carries afferents from the pontine nuclei

Inferior cerebellar peduncle:

Restiform body: Carries afferents from the inferior olivary nucleus, dorsal spinocerebellar tract from Clarke’s column (exteroceptors from below T1), lateral cuneate nucleus from fasciculus cuneatus (exteroceptors from above T1), and arcuate nuclei

Juxtarestiform body: Carries bidirectional connections with the vestibular nuclei

Box 1.17

Triangle of Mollaret—Bidirectional connections between ipsilateral red nucleus, ipsilateral inferior olivary complex, and contralateral dentate nucleus

Brainstem

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(2)disrupted sleep–wake cycles

(3)occasionally CN III palsy

ii.specific lesions have been located bilaterally in the medial substantia nigra pars reticulata; symptoms may relate to dysfunction of the mesencephalic reticular formation with disinhibition of dream generation

f. top-o’-the-basilar syndrome

i.symptoms

(1)somnolence, coma

(2)amnesia

(3)visual and ophthalmologic dysfunction: hemianopia or complete vision loss; Anton’s syndrome, Balint’s syndrome, Parinaud’s syndrome (see pp. 43, 45)

(4)peduncular hallucinosis

ii.caused by occlusion of the basilar tip, leading to infarction of the tegmentum, medial thalamus, and parietal and occipital lobes; may be unilateral or bilateral

g.midbrain locked-in syndrome—symptoms are as per pontine locked-in syndrome (quadriparesis, anarthria) except that no voluntary eye movements are preserved; caused by bilateral lesions of the cerebral peduncles

h.hemiparkinsonism, contralateral to lesions of the substantia nigra pars compacta

i.hemiplegia

4.Dorsal mesencephalon syndromes

a.Nothnagel’s syndrome—symptoms include ipsilateral ataxia, vertical gaze palsy, and ipsilateral CN III palsy; caused by lesions in the pretectum involving the fibers of CN III and the superior cerebellar peduncle (Box 1.18)

b.ophthalmologic syndromes (see p. 44)—Parinaud’s syndrome, syndrome of the Sylvian aqueduct, retraction nystagmus, vertical one-and-a-half syndrome

Box 1.18

Different than Claude’s syndrome, which has contralateral ataxia

Brainstem

Table 1–5 Other Trigeminal Reflexes

b.mesencephalic trigeminal nucleus: contains the primary sensory neurons for the muscle spindles and Golgi tendon organs of the masticatory muscles; forms monosynaptic connection with the motor trigeminal nucleus to produce the jaw jerk reflex (Table 1–5)

3.Other centers

a.locus coeruleus (see p. 48)

b.auditory nuclei (see p. 48): nucleus of the lateral lemniscus, nucleus of the trapezoid body, superior olivary nucleus

4.Pathophysiology: the ventral pontine syndromes

a.ataxic-hemiparesis/clumsy hand-dysarthria syndrome—symptoms include contralateral ataxia and weakness, dysarthria, and nystagmus

i.classically a pontine lesion, but can also occur with thalamocapsular or internal capsule/basal ganglia lesions

ii.may involve ipsilateral sensory loss, typically in the face, which is strongly indicative of a lesion in the thalamus

iii.usually the weakness is worse in the lower extremity, and the ataxia is worse in the upper

b.Millard-Gubler syndrome—symptoms include ipsilateral facial weakness, horizontal diplopia from CN VI palsy, and contralateral weakness of the upper and lower extremities; caused by lesions involving the facial nucleus, CN VI fibers, and the corticospinal tract

c.ventromedial pontine syndrome/Raymond’s syndrome—as per MillardGubler syndrome, but may also involve ipsilateral ataxia with middle cerebellar peduncle involvement and ipsilateral facial hemisensory loss with CN V root involvement

d.pseudobulbar palsy—dysarthria, dysphagia, unior bilateral facial weakness, extremity weakness, and emotional behaviors often without conscious perception of the emotion; caused by bilateral injury of the corticobulbar fibers that disconnects brainstem motor nuclei from the cortex

e.pontine locked-in syndrome—symptoms include weakness in all extremities, aphonia due to bilateral corticobulbar tract injury, and bilateral loss of horizontal eye movements with preservation of vertical eye movements; caused by bilateral ventral pontine lesions that involve the corticospinal and corticobulbar tracts, and bilateral CN VI fibers

f.hemiplegia—has a tendency to affect parts of the corticospinal tract (e.g., a single limb) because it is divided by the pontine nuclei

5.Pathophysiology: the dorsal pontine syndromes

a.Marie-Foix syndrome—symptoms include contralateral hemiparesis, ipsilateral ataxia, and a variable loss of small-fiber sensation; caused by lesions of the corticospinal tract, middle cerebellar peduncle, and spinothalamic tract

b.Foville’s syndrome—symptoms include ipsilateral facial weakness and lateral rectus weakness; caused by lesions involving the facial nucleus and abducens nucleus

c.Raymond-Gestan syndrome—symptoms include ipsilateral ataxia, contralateral pan-modal sensory loss, ipsilateral facial weakness, and horizontal diplopia from ipsilateral lateral rectus weakness; lesions involve the middle cerebellar peduncle, medial lemniscus and spinothalamic tract, facial nucleus or CN VII fibers, and abducens nucleus

d.internuclear ophthalmoplegia, one-and-a-half syndrome (see p. 45)

Brainstem

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b.arcuate nuclei: essentially are ectopic pontine nuclei (i.e., cerebellar relay nuclei) that send afferents to that cerebellum via the inferior cerebellar peduncle

c.perihypoglossal nuclei, which are accessory ocular motor nuclei (see

p.44)

4.Pathophysiology: The medullary syndromes

a.hemiplegia cruciata/cruciate paralysis—symptoms include ipsilateral lower extremity and contralateral upper extremity weakness, wherein the upper extremity weakness is worse than the lower extremity weakness; also may involve respiratory impairment, hypotension, sensory loss in the neck and posterior head, facial sensory loss in an onion-skin pattern (from spinal trigeminal nucleus injury; and/or lower cranial neuropathies (CN IX–XI)

i.caused by lesions of the lateral aspect of the corticospinal tract decussation where upper extremity fibers decussate rostral to the lower extremity fibers

b.ventromedial medullary syndrome/Dejerine’s syndrome—symptoms include contralateral upper and lower extremity weakness sparing the face, ipsilateral weakness of the tongue, and ipsilateral loss of vibratory and position sense; caused by lesions involving the corticospinal tract, anterior CN XII fibers, and medial lemniscus

c.dorsolateral medullary syndrome/Wallenberg’s syndrome

i.symptoms

(1)ipsilateral: Horner’s syndrome; ataxia; loss of small-fiber sensation in the face; transient facial pain; weakness of the palate, larynx, and pharynx causing dysarthria and dysphonia

(2)contralateral: loss of small-fiber sensation in body

(3)hiccups

ii.caused by lesions of the lateral ponto-mesencephalic junction, usually vertebral artery infarction more so than posterior inferior cerebellar artery (PICA) infarction

d.hemimedullary syndrome/Babinski-Nageotte syndrome—the combination of ventromedial and dorsolateral medullary syndromes

D.Reticular Formation

1.Anatomy: a diffuse group of intrinsic brainstem and diencephalic neurons of varying size and shape that are separated by myelinated axons projecting in all directions {reticulum}; extends from the caudal medulla through the pons and mesencephalon into the diencephalon up to the posterior hypothalamus and thalamus (midline, intralaminar, and reticular nuclei)

2.Subdivisions and key nuclei

a.mesencephalic reticular formation

i.dorsal raphe nucleus: sends serotonergic projections to most of the forebrain and basal ganglia; many neurons colocalize serotonin with substance P

ii.pedunculopontine tegmental nucleus (acetylcholinergic): related to basal ganglia circuits

iii.ventral tegmental area (dopaminergic): related to the nucleus accumbens

b.pontine reticular formation

i.locus coeruleus: supplies norepinephrine to most of the brain and spinal cord except for the hypothalamus and the preganglionic sympathetic neurons of the spinal cord intermediolateral cell column, which receive adrenergic innervation from the medulla

(1)degenerates in conditions that affect other pigmented neurons (e.g., Parkinson’s disease) or in dementing disorders (e.g., Alzheimer’s disease)

ii.nucleus reticularis pontis: controls convergent and divergent eye movements and forms the ventral reticulospinal tract

iii.paramedian pontine reticular formation

c.medullary reticular formation (Box 1.19)

i.lateral reticular nucleus

ii.medullary raphe nuclei (pallidus, obscurus, magnus): forms serotonergic projections to the diencephalon, brainstem, and spinal cord, but not to the telencephalon; many neurons colocalize serotonin with substance P or galanin

iii.nucleus gigantocellularis

3.Afferents

a.spinoreticulothalamic tract, which carries poorly localizable pain sensation to the intralaminar thalamic nucleus and reticular formation

b.corticospinal and corticobulbar tracts

c.sensory and autonomic brainstem nuclei; fastigial nucleus; hypothalamus

4.Efferents

a.sensory and motor brainstem nuclei; cerebellum

b.ventral and lateral reticulospinal tracts

i.ventral reticulospinal tract: formed by projections from the nucleus reticularis pontis; has ipsilateral projections that are generally excitatory upon spinal motoneurons

ii.lateral reticulospinal tract: formed by projections from the nucleus gigantocellularis; has ipsilateral and contralateral projections that are inhibitory upon spinal motoneurons, causing atonia during REM sleep

c.spinal cord: nucleus raphe magnus reduces pain sensation via projections to the spinal trigeminal nucleus and posterior horn of spinal cord (endogenous analgesic systems)

i.the nucleus raphe magnus is regulated by the periaqueductal gray, which is itself regulated by the hypothalamus and amygdala

d.autonomic control centers

e.ascending reticular activating system (ARAS) and non-ARAS sleep centers

IX. Spinal Cord

1.Long tracts (Fig. 1–23) a. anterior funiculus

i.spinothalamic tract/anterolateral system: formed by axons of secondorder neurons located in the contralateral Rexed laminae I, VI, and VII, which decussate as they ascend a few spinal cord levels

(1)fibers are arranged somatotopically in the spinal cord and also by modality (pain fibers are located anteriorly, temperature fibers are located posteriorly)

(2)carries localizable pain sensation; the spinoreticulothalamic tract carries poorly localizable pain sensation and terminates in the reticular formation and intralaminar nuclei of the thalamus

ii.anterior corticospinal tract

iii.medial longitudinal fasciculus: carries descending fibers to the cervical and upper thoracic spinal cord from the motor nuclei of the ocular muscles, nuclei of the auditory pathway, and vestibular nuclei (all of which control head positioning)

iv.vestibulospinal tracts (see p. 50): facilitates extensor antigravity muscle tone

v.ventral and lateral reticulospinal tracts

Box 1.19

The paramedian pontine reticular formation and the lateral reticular nuclei are also known as the precerebellar nuclei of the reticular formation, which form mossy fiber inputs to the cerebellum.

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b.lateral funiculus

i.lateral corticospinal tract (see p. 3): composed of projections from the

(1)primary motor cortex (Brodmann area 4) and supplementary motor area and premotor cortex (Brodmann area 6), which terminate in the anterior horn

(2)primary somatosensory cortex (Brodmann areas 3,1,2): terminates in Rexed lamina IV; modulates ascending sensory input

ii.rubrospinal tract: decussates immediately after leaving the red nucleus; projects to the anterior horn only in the upper cervical spinal cord levels

iii.spinocerebellar tracts: carry unconscious proprioception, exteroception, and somatosensory information

spinal cord levels below T1; projects to the anterior cerebellar lobe via the inferior cerebellar peduncle

(2)ventral spinocerebellar tract: originates in contralateral Rexed laminae V–VII (lumbosacral levels), projects to the anterior cerebellar lobe via the superior cerebellar peduncle

2.Posterior funiculus: The dorsal columns, that is, the fasciculus gracilis (from lower thoracic, lumbar, and sacral spinal cord) and fasciculus cuneatus (from the spinal cord above T6)

a.both fasciculi are arranged somatotopically and according to modality (pressure and vibration are superficial, proprioception and touch are deep)

b.carry sensation for conscious proprioception, vibration, and discriminative touch (e.g., two-point discrimination, stereognosis, textures)

3.Gray matter

a.dorsal horn: important laminae include

i.substantia gelatinosa (Rexed lamina II): contains interneurons that release opioid agonists thereby limiting release of substance P from pain-sensitive dorsal root fibers

(1)supraspinal pain modulation is provided by descending norepinephrine fibers from the pontine A7 nucleus (not the locus coeruleus) and serotonergic fibers from the nucleus raphe magnus

ii.nucleus proprius (Rexed lamina III and IV): GABAergic interneurons

iii.lamina V projects into the spinothalamic tract (with laminae I and VII)

b.intermediate zone (Rexed lamina VII)

i.intermediolateral cell column: receives descending excitatory aminergic input from medullary C/A2 and A5 aminergic nuclei, and inhibitory serotonergic input from the medullary raphe nuclei

ii.Clarke’s column: located medial to the intermediolateral cell column between T1 and L3 spinal cord levels; relays proprioceptive and tactile sensory inputs from spinal cord levels below T1 (from the trunk and lower limbs) to the cerebellum through the dorsal spinocerebellar tract

c. anterior horn (Rexed lamina VIII, IX)

i.motoneurons

(1)subtypes

(a)-I motoneurons: have large cell bodies; innervate fatigable and fatigue-resistant fast-twitch muscle fibers

(b)-II motoneurons: have small cell bodies; innervate fatigueresistant slow-twitch muscle fibers

(c)motoneuron/fusimotor neurons: have very small cell bodies; innervate the intrafusal muscle fibers of the muscle spindles

(2)somatotopic arrangement of motoneurons (Fig. 1–24)

(3)modulated by excitatory fibers from locus coeruleus and inhibitory fibers from the medullary raphe nuclei

ii.interneurons: all are inhibitory, and use glycine GABA

(1)Ia “reciprocal” interneurons: receive direct excitatory input from sensory Ia (glutamate) muscle spindle afferents of the agonist muscle, and serve to inhibit the motoneurons of the antagonist muscle (e.g., during rapid contraction)

(2)Renshaw cells: innervated by excitatory acetylcholinergic collaterals of the agonist muscle motoneurons, and serve to inhibit those same motoneurons {recurrent inhibition} and the Ia interneurons of the antagonist muscles (i.e., increases antagonist tone)

(3)Ib interneurons: receive direct excitatory input from the sensory Ib afferents of the Golgi tendon organs of the agonist muscle and from cutaneous sensory receptors, and serves to inhibit the agonist muscle (e.g., to limit the force of exploratory touch)

4.Vascular supply (Fig. 1–25): Not continuous along the whole length of the spinal cord, allowing for watershed infarctions

5.Pathophysiology: incomplete spinal cord injuries

a.central cord syndrome—symptoms include bilateral weakness in the upper lower extremities because of involvement of the medial corticospinal tracts (which place fibers to the upper extremity medially) and the lower motoneurons of the cervical spinal cord

i.caused by neck hyperextension that compresses the spinal cord between an anterior osteophytic bone or herniated disk and the posterior ligamentum flavum; the pathological process is not necessarily infarction, but may involve traumatic injury and demyelination

ii.differentiate from cruciate paralysis by the presence of lower motoneuron-type weakness, the absence of facial sensory loss, and the absence of cranial nerve injury

b.anterior cord syndrome—symptoms include bilateral weakness, loss of pain and temperature sense below the level of lesion, and impaired bowel and bladder control; proprioception, vibration, and light touch are preserved

i.caused by lesions of the entire cord except the dorsal columns

ii.may develop painful dyesthesias below the level of lesion

Figure 1–24 Somatotopic organization of the spinal gray matter. (From Kahle W, Color Atlas/Text of Human Anatomy, Vol. 3: Nervous System and Sensory Organs. 4th ed. Stuttgart, Germany: Georg Thieme; 1993:47, Fig. C. Reprinted by permission.)

Figure 1–25 Vascular anatomy of the spinal cord. (From Rohkamm R, Color Atlas of Neurology. Stuttgart, Germany: Georg Thieme; 2004:23).

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Table 1–6 Conus Medullaris and Cauda Equina Syndromes

c.posterior cord syndrome—symptoms include loss of proprioception and vibratory sense below the level of lesion, and complete sensory loss in the dermatome at the level of the lesion (i.e., also involving small fiber sensation); caused by lesions of the dorsal columns

d.Brown-Sequard/hemisection syndrome—symptoms include ipsilateral sensory loss for vibration and proprioception, ipsilateral hemiplegia, and contralateral loss of pain and temperature sensation; touch is generally preserved due to representation in multiple bilateral ascending tracts

i.pain and temperature sensory loss tends to occur 1–2 levels below the level of vibration and proprioception loss because the projections of the second-order sensory neurons of the spinothalamic tracts ascend a few levels as they decussate

e.conus medullaris and cauda equina syndromes (Table 1–6)

X. Cranial Nerves

1.Anatomy

a.CN II (see p. 39); CN III, IV, VI (see p. 44)

b.CN VII: (Fig. 1–26)

c.CN XI: (Fig. 1–27)

2.Cranial nerve ganglia (Table 1–7)

3.Specific disorders of cranial nerves

a.optic neuritis ischemic optic neuropathy (see p. 38)

b.trigeminal neuralgia, glossopharyngeal neuralgia

c.hemifacial spasm—symptoms include irregular, repetitive contractions of the muscles of half of the face (including the platysma) that are induced by voluntary facial movements; often begins in the orbicularis oculi, and spreads to the other facial muscles over time

i.caused by compressive lesions of CN VII (e.g., tumor, basilar artery aneurysm) or as a complication of a resolving Bell’s palsy

ii.treat with antiepileptic drugs (carbamazepine) or surgical decompression

d.Bell’s palsy—there is generally no hyperacusis; loss of the stapedius reflex does not cause hyperacusis to normal sounds; principles of neurologic localization do not apply in Bell’s palsy; involvement of the stapedius or GSPN (dry eye) is an indication of greater severity of the lesion, not an indication of location of the lesion; the entire nerve is inflamed; the greatest degree of compression seems to be in the labyrinthine segment, where the fallopian canal is the narrowest

i.epidemiology: increased risk in diabetics but not during pregnancy

ii.symptoms: retroauricular pain that precedes facial weakness by 1–2 days; the facial weakness is relatively acute in onset but it increases over 2–5-day period

(1)associated symptoms (hyperacusis, loss of taste sensation) occur depending upon the segment of CN VII involved (Fig. 1–26)

Figure 1–26 Fiber components of CN VII and the nervus intermedius. Damage in different segments of the nerve (numbered 1–5) causes different neurological symptoms because of the involved nerve branches. The greater petrosal nerve carries parasympathetics to the lacrimal and nasal glands. The stapedius nerve acts to dampen the tympanic membrane oscillation. The chorda tympani carries taste sensation from the anterior tongue. (From Duus P, Topical Diagnosis in Neurology. Stuttgart, Germany: Georg Thieme; 1998:113, Fig. 3.35. Reprinted by permission.)

Figure 1–27 Course of CN XI. (From Duus P, Topical Diagnosis in Neurology. Stuttgart, Germany:

Georg Thieme; 1998:130, Fig. 3.43. Reprinted by permission.)

Table 1–7 Cranial Nerve Ganglia

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Table 1–8 Cranial Nerve Syndromes

iii.treatment: protection and lubrication of the ipsilateral eye; 4–10-day course of prednisone antiherpetic drug (acyclovir, famcyclovir), started within 1 week of symptomatic onset

(1)no evidence in support of CN VII decompression surgery

iv.prognosis: 75% recover within 3 weeks; better outcomes occur in cases with partial weakness and a rapid recovery of taste

(1)increased tone of the facial muscles after CN VII regeneration may give the appearance that the facial palsy was on the opposite side

(2)facial synkinesis—aberrant regeneration of CN VII fibers that innervate the wrong target, often producing unintentional blinking, twitching, tearing, or snarling

4.Cranial nerve syndromes (Table 1–8)

Ventricle System and Cerebrospinal Fluid (CSF)

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Table 1–9 Bladder Dysfunction

(3)symptoms (in order of appearance)

(a)gait disturbance: Bruns’ frontal lobe ataxia (see p. 5)

(b)dementia (60%): predominant short-term memory impairment

(c)urinary incontinence from a spastic bladder; urinary urgency may precede incontinence

(4)specific diagnostic testing: no test exhibits high diagnostic accuracy

(a)lumbar puncture

(i)demonstrates normal pressure but continuous CSF pressure monitoring may exhibit Lundberg B waves or transient pressures 20 mm Hg

(ii)symptoms must improve with large-volume CSF drainage

(iii)measurement of resistance with fluid infusion into subarachnoid space is correlated with symptoms but is not predictive of shunting outcome

(b)radionuclide cisternography: retention of contrast in the ventricles 24 hours after administration is not useful for establishing the diagnosis or predicting the clinical response to shunting

(c)MRI CSF flow study: absence of CSF flow near the cerebral aqueduct does not predict the clinical response to shunting

(5)treatment: low-pressure ( 3-mm opening pressure) ventriculoperitoneal shunt

(a)patient should be sat upright slowly over several days after placement

(b)lumboperitoneal shunts generally results in overshunting and have high complication rates

(6)prognosis: incontinence and gait generally improve more than dementia

(a)responsiveness to shunting is prediced by

(i)the presence of the classic triad of symptoms

(ii)clinical improvement after lumbar puncture

(iii)opening pressure 7 mm Hg

(iv)the presence of high transient pressures on continuous CSF pressure monitoring

(v)the absence of ischemic changes on MRI

iii.hydrocephalus ex vacuo—dilation of the ventricular system due to brain atrophy that can be either diffuse or focal

Figure 1–29 Photoreception in the retina. (From Koolman J, Rohm KH, Color Atlas of Biochemistry. Stuttgart, Germany: Georg Thieme; 1996:326. Reprinted by permission.)

XIII. Neuroophthalmology

A. The Sensory Visual System

1.Retina

a.vision reception (Fig. 1–29)

b.subtypes of retinal fiber bundles (Fig. 1–30)

c.pathophysiology: retinal fiber loss causes

i.decreased visual acuity with papillomacular bundle injury

ii.scotomata (Box 1.20)

(1)scotomata from papillomacular bundle injury (Fig. 1–31): central, centrocecal (a central scotoma that connects to the blind spot), or paracentral scotoma

(2)scotomata from arcuate bundle injury (Fig. 1–32): all connect with the physiological blind spot

Box 1.20

Failure of defect to connect to the blind spot suggests the lesion is retro-chiasmatic.

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40

b.pathophysiology: large lesions in Meyer’s loop cause superior homonymous quadrantic (“pie in the sky”) field defects, whereas small lesions cause scotoma-like defects; lesions in the mesial parietal lobe cause inferior homonymous quadrantic field defects (a defect that is more likely to be caused by occipital lobe lesions)

8.Primary visual cortex (Brodmann area 17/visual area I)

a.representation of visual fields on the primary visual cortex

i.visual field representation is completely inverted on the occipital cortex (e.g., the superior visual field is below calcarine fissure; the inner retina (macula) is represented on the outermost occipital cortex)

ii.macular retina has disproportionately large area of representation on the visual cortex

b.blood supply

i.outside of macular region: calcarine artery branch of the PCA

ii.macular region/pole of occipital cortex: in addition to the PCA, it may receive collaterals from the meninges that could account for the sparing of macular vision that can occur after bilateral occipital lobe infarcts

c.pathophysiology: highly congruous visual field defects; vision loss does not involve neglect, asymmetry of optokinetic nystagmus, or loss of blinking to threat

d.diagnostic testing

i.visual evoked potentials (VEP): the potential derived from occipital cortex caused by stimulation of the retina (e.g., with a strobe light or reversal of a checkerboard pattern) (Fig. 1–36)

A

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(1)requires time-locked averaging, which averages-out the background EEG signal

(2)VEP predominantly tests macular vision because the macula has a disproportionately large cortical representation and is closer to the electrode

(3)VEP uses

(a)multiple sclerosis: prolonged latency of the positive-deflection at 100 ms (P100) can be considered as a subclinical demyelinating event, although it also occurs with other demyelinating diseases (e.g., vitamin B12 deficiency, spinocerebellar degeneration)

(b)optic neuropathy: reduced P100 amplitude is suggestive of ischemia, although it can also represent nerve compression or toxic neuropathies

(c)factitious disorders: normal VEP and electroretinogram make the subjective complaint of vision loss highly suspect

9.Association visual cortex

a.subdivisions

i.Brodmann area 18/visual area II

ii.Brodmann area 19/visual area III

iii.Brodmann area 36/visual area IV

iv.Brodmann area 37/visual area V: involved in the perception of motion {kinetopsia}, which may also involve visual area III

b.pathophysiology

i.achromatopsia (Box 1.21): caused by lesions in visual area IV (occipitotemporal junction of the fusiform and lingual gyri)

(1)hemiachromatopsia often occurs with a superior quadrantopsia and/or prosopagnosia

(2)color vision is also compromised early in disorders of the optic nerve and chiasm (particularly red perception) and may persist even if acuity returns

ii.akinetopsia: the inability to perceive moving objects in the contralateral visual hemifield, which suddenly appear when they become stationary; caused by lesions of visual area V

iii.visual neglect: the inability to perceive visual stimuli in the affected visual field when subjected to bilateral stimulation, but without outright vision loss; typified by patient complaints of running into objects on the neglected side

(1)associated with abnormal optokinetic nystagmus, and with abnormal drawing and copying abilities when the lesion is in the nondominant hemisphere

(2)caused by lesions in Brodmann areas 18 or 19/visual areas II or III

iv.prosopagnosia: the inability to recognize familiar faces; usually caused by bilateral lesions of the fusiform gyrus, although it may also occur with large injuries in the nondominant temporal lobe (e.g., as in progressive prosopagnosia, a subtype of frontotemporal lobar degeneration)

v.Anton’s syndrome—the denial of complete blindness (i.e., anosognosia for blindness) with confabulation

(1)caused by lesions that produce complete vision loss (typically bilateral medial occipital lobe lesions, although the lesions may be in the anterior visual system) in conjunction with

(a)bilateral lateral occipitoparietal cortex lesions (visual areas II and III)

(b)thalamic lesions, as in the top-o’-the-basilar syndrome

Box 1.21

Blue/yellow deficits occur early in glaucoma.

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44

b.convergence movements involving both medial rectus muscles are coordinated by interneurons located within the medial rectus subdivision of the oculomotor nucleus

c.pathophysiology: lesions of the oculomotor nucleus impair the ipsilateral ocular muscles innervated by CN III except for the superior rectus, which is contralaterally innervated; ptosis occurs only with lesions of the central caudal subdivision of the oculomotor nucleus, and is always bilateral

3.Trochlear nucleus: Efferent fibers decussate in the medullary velum and innervate the contralateral superior oblique muscle, which acts to move the eye downward when it is fully adducted

a.lesions cause extorsion of the affected eye and head tilting to the opposite shoulder

b.test for CN IV palsy in the presence of CN III palsy by having the patient attempt to look downward with the affected eye in abduction, which should produce a clockwise rotation of the eye if CN IV is functional

4.Abducens nucleus (Box 1.22)

a.types of neurons include

i.motoneurons projecting to the ipsilateral lateral rectus muscle

ii.neurons projecting to the contralateral oculomotor nucleus via the medial longitudinal fasciculus; these neurons are regulated by the paramedian pontine reticular formation (PPRF) to direct horizontal conjugate eye movements

(1)nucleus reticularis pontis of the pontine reticular formation coordinates the oculomotor and abducens nuclei during convergence and divergence

b.pathophysiology

i.internuclear ophthalmoplegia

(1)symptoms: lack of contralateral eye adduction during conjugate lateral gaze, but not during convergence; nystagmus in both eyes (greater in abducted eye) during conjugate lateral gaze

(2)caused by lesions of the medial longitudinal fasciculus in the pons, which is often bilateral due to the close proximity of the two fasciculi

ii.one-and-a-half syndrome—caused by lesions of both the medial longitudinal fasciculi and the abducens nucleus (an intranuclear ophthalmoplegia); symptoms include bilateral inability to adduct the eyes during conjugate lateral gaze and ipsilateral lateral rectus muscle weakness

5.Accessory ocular motor nuclei

a.mesencephalic accessory ocular motor nuclei

i.rostral interstitial nucleus of the medial longitudinal fasciculus (riMLF): regulates vertical conjugate eye movements

(1)neurons controlling upward gaze (often specifically called the nucleus of the posterior commissure) project through the tectum (i.e., dorsal to the aqueduct) to the oculomotor and trochlear nuclei, therefore they are more sensitive to pineal masses causing Parinaud’s syndrome

(2)neurons controlling downward gaze project through the tegmentum (i.e., ventral to the aqueduct) to the oculomotor and trochlear nuclei

ii.interstitial nucleus of Cajal: involved in maintaining vertical gaze

iii.pretectal nucleus: regulates pupil light reaction; receives direct optic nerve input

(1)pathophysiology: Argyll-Robertson pupil, which is a functional elimination of the light reaction circuit without impairment of pupil constriction during accommodation

iv.nucleus of Darkschewitsch, which has an unknown function

b.pontine and medullary accessory ocular motor nuclei

Box 1.22

Near Triad Reflex

Convergence

Lens accommodation

Pupil constriction

i.paramedian pontine reticular formation (PPRF): irregulates horizontal conjugate eye movements acting via abducens nucleus

(1)excitatory burst neurons initiate saccode

(2)inhibitory burst neurons suppress contralateral abducens nucleus

(3)omnipause neurons block burst neurons and prevent saccodes

ii.perihypoglossal nuclei: have poorly defined roles in conjugate eye movements; not related to tongue movements

iii.nucleus prepositus hypoglossi: involved in maintenance of horizontal gaze along with the medial vestibular nucleus

iv.nucleus interpositus and the nucleus of Roller, which have unclear functions

c.pathophysiology involving the accessory ocular motor nuclei

i.Parinaud’s syndrome—caused by pineal-region masses or hydrocephalus that injures the pretectal region

(1)symptoms include

(a)supranuclear upgaze palsy, but preserved oculocephalic and oculovestibular-induced upgaze

(b)eyelid retraction {Collier’s sign} and lid lag with downgaze {setting sun sign}

(c)loss of convergence and accommodation

(d)Argyll-Robertson pupil

(e)convergence spasm and retraction nystagmus

(f)skew deviation

ii.syndrome of the Sylvian aqueduct—Parinaud’s syndrome also with a downgaze palsy

iii.vertical one-and-a-half syndrome—symptoms include bilateral upgaze palsy and ipsilateral monocular downgaze palsy; caused by poorly localized pretectal lesions

iv.skew deviation/vertical strabismus—symptoms include the perception of tilting of the visual fields, which is often compensated for by a head tilt

(1)caused by an imbalance in the vestibular input from lesions anywhere in the vestibular complex, vestibular division of CN VIII, or brain regions dealing with vestibular sensation including cortex; can also be seen with diffuse intracranial processes (e.g., elevated intracranial pressure, metabolic encephalopathy)

(a)variance of the skew deviation in different gaze positions suggests medullary lesion

(b)slowly alternating skew deviation suggests a mesencephalic tectal lesion

6.Superior colliculus: controls saccadic eye movements via projections to the PPRF and riMLF, and regulates gaze fixation on visual targets

7.Cerebellum: coordinates ballistic eye movement and braking during saccades

a.vermis and superior cerebellar peduncle lesions produce hypermetric contralateral saccades and hypometric ipsilateral saccades, which is the opposite of what fastigial nucleus lesions produce

b.flocculus lesions impair ipsilateral smooth pursuit movements and the ability to maintain gaze fixation after a saccade

8.Pulvinar (thalamus): involved in the maintenance and shifting of visual attention; promotes contralateral saccadic eye movements

9.Ocular motor circuit of the basal ganglia (see Table 1–2): acts selectively to gait all types of saccadic eye movements

10.Cortical gaze centers

a.frontal eye field (Brodmann area 8): directs intentional saccades and pursuit movements contralaterally; has separate neurons for selecting the new eye position and for actually moving the eyes

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i.lesions cause ipsilateral gaze preference acutely, which resolves within days

b.parietal eye field (Brodmann area 39 in the angular gyrus): directs unconscious saccades toward novel objects in the visual field, and mediates reflex pursuit of a visual target; visual area III of the occipital cortex may assist in reflex pursuit movements as well

i.the right parietal eye field is involved in bilaterally directed saccades whereas the left parietal eye field is involved only in contralaterally directed saccades, although lesions or either side cause an ipsilateral gaze preference

c.supplementary motor cortex (Brodmann area 6): involved in the generation of multi-step saccadic eye movements, and in suppressing unconscious saccades

d.pathophysiology

i.gaze deviation: oculocephalic/oculocaloric testing determines if the gaze limitation observed during voluntary eye movements can be overcome by involuntary brainstem mechanisms (i.e., the vestibular system); if a gaze palsy can be overcome by oculocephalic/oculocaloric testing, it is caused by a lesions above the brainstem (i.e., a supranuclear gaze palsy)

11.Localizable nystagmus syndromes (Fig. 1–39)

12.Inherited ocular motor disorders

a.Kearns-Sayre syndrome

i.pathophysiology: usually caused by a large deletion in the mitochondrial genome; sporadic inheritance, unlike other mitochondrial diseases

(1)number of mitochondria in a cell may be increased as a compensatory reaction to their poor function

(2)severity of symptoms is proportionate to the number of affected mitochondria

ii.symptoms: develops in childhood

(1)progressive ophthalmoplegia

(2)retinitis pigmentosa

(3)sensorineural hearing loss

(4)weakness, myalgias, and spasticity

(5)mental retardation

(6)cardiac arrhythmia; endocrinopathy from hypothalamic dysfunction; short stature

iii.diagnostic testing: muscle biopsy demonstrates ragged red fibers on light microscopy and distorted

mitochondria on electron microscopy; cerebrospinal fluid analysis demonstrates increased protein and decreased folate levels

iv.treatment: multivitamin supplementation

b.Leigh’s disease

(1)pyruvate dehydrogenase deficiency (25%): the enzyme normally converts pyruvate to citrate in the Kreb’s cycle, and is located in the mitochondrion

(2)cyclooxygenase deficiency (25%)

(3)mitochondrial respiratory chain complex I (25%) or V (15%) deficiencies

(4)point mutations in the mito-

ii.histology: necrosis of the basal ganglia and periaqueductal gray

iii.symptoms: onset is usually in infancy; may have a progressive or episodic course

(1)apnea, particularly sleep apnea (one of the few causes of central sleep apnea)

(2)ophthalmoplegia (mostly with cyclooxygenase deficiency)

(3)ataxia; spasticity

(4)peripheral neuropathy

(6)retinitis pigmentosa (only with complex V deficiency)

iv.diagnostic testing

(1)lactate and pyruvate are elevated only after glucose challenge

(2)enyzme and genetic analysis

v.treatment: carnitine, coenzyme Q10, and B-complex vitamin sup-

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Thalamus

Superior olivary nucleus

Anterior cochlear nucleus

Pons

Cochlear portion of CN VIII

Posterior cochlear nucleus

Trapezoid body

Medulla

Medial geniculate body

Brachium of the inferior colliculus

Inferior Colliculus

Commissure of the inferior colliculus

Nucleus of the lateral lemniscus

Lateral lemniscus

Nucleus of the trapezoid body

Posterior acoustic stria

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*Includes accessory ocular motor nuclei.

b.vestibular thalamus: there is no clear target for vestibular inputs, although a thalamic intermediary is very likely

c.vestibular cortex: vestibular sensation is likely represented in

i.Brodmann area 2v, located adjacent to the inferior edge of the lateral surface of Brodmann area 2 in the parietal lobe

ii.Brodmann areas 41 and 42, adjacent to the primary auditory cortex in the temporal lobe

C. Neurotology Pathophysiology

1.Hearing loss

a.conductive hearing loss—occurs with pathological process of the external acoustic meatus or middle ear structures; produces a uniform hearing loss across all frequencies that is usually associated with low-frequency tinnitus; conductive hearing losses are equal in all frequencies or may involve the low frequencies mostly; tinnitus is usually not present, but may be of any perceived frequency

i.the Rinne test produces a louder sound with bone conduction than with air conduction, and the Weber test lateralizes to the diseased ear

b.sensorineural hearing loss—caused by diseases of the cochlea more commonly than injury to CN VIII; produces hearing loss in the high-frequency ranges, and exhibits decreased sensitivity to low and mid-intensity sounds but increased sensitivity to high-intensity sounds; usually associated with high-frequency tinnitus; there are many patterns of SNHL; flat and high frequency patterns are more common; a low frequency SNHL is characteristic of cochlear hydrops

i.the Rinne test produces a louder sound with air conduction than with bone conduction, and the Weber test lateralizes to the normal ear

c.treatment

i.glucocorticoids (typically prednisone 1 mg/kg for 7 days) for rapid hearing loss; for sudden sensorineural hearing loss, after otolaryngic and audiologic evaluations

ii.hearing aids, for either type of hearing loss

iii.corrective surgical procedures for conductive hearing loss

2.Tinnitus—Associated with some degree of hearing loss in 95% of cases (Box 1.24)

a.generally tinnitus is only perceived by the affected individual; tinnitus that can be perceived by the examiner usually relates to muscular contractions of the nasopharynx (e.g., palatal myoclonus) or is transmitted from the carotid artery; tinnitus of vascular origin may be due to mild benign intracranial hypertension, primary or metastatic tumors, intracranial or extracranial vascular lesions

Box 1.24

Tinnitus is not the same as otoacoustic emissions, which are sounds that are normally produced by the outer hair cells of the cochlea in response to an auditory stimulus.

b.treatment

i.masking sounds (e.g., white noise generators) to interrupt the tinnitus

ii.hearing aids for hearing loss

iii.antidepressants, alprazolam

iv.biofeedback and stress management

3.Other abnormalities of hearing

a.pure word deafness/auditory agnosia—caused by injury to the dominantside monomodal auditory association cortex

i.reading and writing are intact, therefore it is not an aphasia

ii.comprehension of nonverbal sounds are intact

b.impaired ability to understand nonverbal sounds occurs with injury to nondominant monomodal auditory association area

c.cortical auditory hallucinosis—tend to be formed hallucinations with identifiable sounds, in contrast to pontine auditory hallucinosis

i.poorly localizes to the superior temporal gyrus in the dominant hemisphere; typically occur in the context of temporal lobe seizures in conjunction with other types of hallucinations (olfactory, gustatory) (Box 1.25)

d.paracusis—distortions in the perception of timbre, tone, or loudness in the presence of otherwise normal hearing; can occur with lesions anywhere in the temporal lobe

e.diplacusis—a difference in perception of sound between the two ears that causes a single sound to be heard as two separate sounds; most commonly a cochlear injury

f.hyperacusis—the perception of abnormal growth of loudness, which typically occurs with loss of outer hair cells, e.g., classic Meniere’s disease (Box 1.26)

4.Vertigo: Distinguishing central versus peripheral vertigo (Table 1–11)

a.benign paroxysmal positional vertigo (BPPV)

i.pathophysiology: caused either by movement of free otoliths in a semicircular canal (usually the posterior), or else by accumulations of basophilic material in the cupula of a semicircular canal that cause it to bend when the head is in certain positions; not caused by having the head in any particular position; caused by an angular acceleration in the plane of the semicircular canal that has the lesion

Table 1–11 Central versus Peripheral Vertigo

*The severity, exacerbation by movement, nausea, and tinnitus are not reliable distinguishing features. Vertigo may occur in isolation with brainstem injuries or in conjunction with only hearing loss due to infarction of the internal auditory artery (a branch of the anterior inferior cerebellar artery).

Abbreviation: BPPV, benign paroxysmal positional vertigo.

Box 1.25

Pontine auditory hallucinosis—Poorly formed sounds that are more complex than just tinnitus (e.g., ringing, buzzing); caused by poorly localized injuries that do not interfere with BAEPs

Box 1.26

Hyperacusis is most commonly caused by injury to the cochlea.

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1 Neuroanatomy

52

(1)15% of cases develop after head trauma, and 15% develop after viral labyrinthitis (i.e., after a period of more intense vertigo)

(2)increased incidence in patients with Meniere’s disease

ii.symptoms: episodes of vertigo lasting 1 minute that are provoked by certain movements (lying down, turning over in bed, flexing or extending the head), although exacerbation by movement is nonspecific for all vertiginous disorders; vertigo typically develops several seconds after the provoking movement

(1)episodes tend to be more severe after awakening

(2)in the elderly, BPPV may last only a few seconds and be provoked only by head turning

iii.diagnostic testing

(1)Dix-Hallpike maneuver: produces 1-minute episodes (typically15 seconds) of nystagmus with a latency of a few seconds; the nystagmus is predominantly torsional but also has a vertical component

(a)sitting upright after the maneuver also causes symptoms and reverses the direction of the nystagmus

(b)repeating the maneuver causes acclimation that requires several minutes to fatigue

(c)unlike all other causes of vertigo, the nystagmus fast phase is toward the side of the bad ear; the nystagmus is torsional and geotropic, i.e., the upper part of the eye in the fast component beats toward the ground when the affected side of the head is moved into the Dix-Hallpike position

(2)caloric testing: normal

iv.treatment (in order of preference)

(1)repositioning maneuvers

(a)Epley maneuver: improves symptoms in 95% of cases within 1 week; decreases the 6-month recurrence rate to 5%

(b)Seamont maneuver: improves symptoms in 90% of cases within 1 month; decreases the 6-month recurrence rate to 5%

(2)antiemetics; vestibular suppressants (meclizine, benzodiazepines, amitriptyline)

(3)habituation exercises

(4)surgical treatments, for medically refractory cases

(a)occlusion of the posterior semicircular canal

(b)transection of vestibular part of CN VIII as it connects with the posterior semicircular canal

v.prognosis: episodes typically occur intermittently over a period of several weeks before spontaneously resolving, although BPPV may be a chronic condition in the elderly; without repositioning treatment, 25% resolve within 1 month

b.Meniere’s disease

i.pathophysiology: may be caused by endolymphatic distention {hydrops} that follows rupture of the membranous labyrinth, which ultimately causes cochlear hair cell death

(1)endolymphatic hydrops and cochlear hair cell loss are not always associated with the symptoms of Meniere’s disease, and may also occur after traumatic inner ear injury, labyrinthitis, or syphilis infection

(2)obvious cochlear hair cell loss occurs only in advanced Meniere’s disease; such cases also exhibit degeneration of other inner ear structures (e.g., atrophy of the cristae and the tectorial membrane)

(3)exhibits rare autosomal dominant and recessive inherited forms

ii.symptoms

(1)episodic symptoms

(a)tinnitus (generally low-pitched) and fullness in the ear, which sometimes precede the symptoms of vertigo and hearing loss by a few hours

(b)vertigo, lasting from 20 minutes to hours

(c)sensorineural hearing loss predominantly in the lowfrequency range that resolves over a period of a few hours

(2)chronic symptoms (present between episodes)

(a)sensorineural hearing loss (low high frequencies): may actually precede the onset of episodic symptoms

(b)mild ataxia late in the disease course; disequilibrium subjectively is more prominent than observable ataxia

iii.diagnostic testing

(1)audiometry demonstrates sensorineural hearing loss, characteristically in low frequencies

(2)caloric testing sometimes demonstrates a reduced sensitivity of the diseased ear to irrigation in cases of unilateral disease

iv.treatment

(1)low-salt diet

(2)medical therapy

(a)episodic treatment: meclizine (Antivert), antiemetics

(b)prophylaxis: diuretics

(3)surgical therapy for medically refractory cases

(a)intratympanic gentamicin

(b)selective vestibular nerve section

(c)endolymphatic sac procedures: usually decompression or endolymphatic fluid shunting into the mastoid

(d)labyrinthectomy, if all hearing is already lost

v.prognosis: 40% will develop some symptoms in the other ear within 5 years, although only 10% will develop the full Meniere’s syndrome in the second ear

(1)recurrence of episodes is highly variable and cases often involve periods of remission

(2)definitive spells usually end when the hearing loss reaches approximately 70 dB and 50% word recognition

c.vestibular neuronitis

i.pathophysiology: likely caused by viral infection of the vestibular part of CN VIII, because it occurs in epidemics; associated with mumps, measles, Epstein-Barr, and herpes zoster viruses

ii.symptoms: continuous vertigo, typically developing after an upper respiratory tract infection and a prodromal period involving the sensation of disequilibrium; does not involve hearing loss (unlike labyrinthitis)

iii.diagnostic testing: caloric testing demonstrates reduced sensitivity of the diseased ear to irrigation

iv.treatment: meclizine (Antivert) and antiemetics for 2–3 days to weeks, followed by vestibular rehabilitation

v.prognosis: spontaneous resolution over several days to weeks; rarely recurs, but inducible vertigo may persist for weeks

d.labyrinthitis

i.pathophysiology: caused by infection of the labyrinth (either bacterial or viral) or by erosion from chronic middle ear inflammation (e.g., from a cholesteatoma)

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1 Neuroanatomy

Table 1–12 Other Diseases Associated with Vertigo

ii.symptoms

(1)continuous vertigo, which is exacerbated by sneezing or the Valsalva maneuver (likely because of the development of a perilymph fistula)

(2)severe sensorineural hearing loss

(3)occasional meningitis-like symptoms

iii.diagnostic testing: temporal bone CT demonstrates bone erosion, mastoiditis, or abscesses; lumbar puncture to evaluate for meningitis

iv.treatment

(1)medical: antibiotics for an identifiable infection

(2)surgical: myringotomy or mastoidectomy for abscess drainage; removal of middle ear masses

e.medications causing vertigo: aminoglycosides, antiepileptics, antihypertensives, sedatives

f.other diseases associated with vertigo (Table 1–12)

2

Vascular Diseases of the

Nervous System

Note: Significant diseases are indicated in bold and syndromes in italics.

I. Ischemic Stroke

1.Subtypes: considering all ischemic strokes

a.30% are likely due to small artery occlusion

b.30% are likely due to large artery thromboembolism

c.20% are likely due to cardioembolism

d.20% are due to other mechanisms or are cryptogenic

2.Epidemiology: ischemic stroke accounts for 80% of all strokes

a.age: the most predictive factor for stroke

b.sex: male predominant disease until age 75

c.race: Blacks and Hispanics have higher stroke rates

3.Risk factors: identification of a risk factor that may have caused the stroke (e.g., atrial fibrillation) does not obviate the need to evaluate the patient for other possible risk factors

a.previous stroke, either clinical or radiographic

b.transient ischemic attack (TIA): 10% 90-day stroke risk, and 25% 90-day risk of TIA, stroke, or myocardial infarction

i.stroke risk is highest within 24–48 hours of TIA, which supports the recommendation of hospital admission and aggressive evaluation of TIA patients

c.intracranial atherosclerosis: 7%/year stroke risk; higher incidence in Blacks, Asians, and Hispanics

d.hypertension: systolic pressures 140 mmHg and diastolic pressures90 mm Hg are independent risk factors for stroke, and stroke risk is proportionate to the degree of hypertension

e.carotid stenosis: the degree of stenosis is proportionate to stroke risk in both symptomatic and asymptomatic patients

f.heart disease (Box 2.1)

i.atrial fibrillation

(1)overall stroke risk 6%/year; stroke risk is higher in chronic atrial fibrillation or atrial fibrillation due to thyroid disease

(a)1%/year stroke risk in patients 65 years old without other risk factors (can be treated with aspirin if need be)

(b)7–18%/year stroke risk in patients with at least one other stroke risk factor (must use Coumadin)

(2)stroke risk is highest at the time of onset of atrial fibrillation; conversion to sinus rhythm without anticoagulation is also high risk

(3)atrial enlargement without fibrillation is also a stroke risk factor

ii.congestive heart failure: stroke risk 4%/year

iii.myocardial infarction: wall motion abnormalities (particularly of the anterior wall) allow intracardiac thrombus formation that is a source of emboli

Ischemic Stroke

Box 2.1

Cardiovascular Procedure Stroke Risks

Angiography 1%

Coronary artery bypass graft 2%

Thoracic aorta operation 7% (higher incidence in emergent operations)

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iv.valve abnormalities (stenosis, calcification, valve replacement) or the presence of coagulant material adherent to a valve (echogenic “strands”)

(1)mitral valve prolapse is unlikely to be a cause of stroke

(2)stroke risk for mechanical valves is greater than for bioprosthetic valves

v.patent foramen ovale: may allow a paradoxical embolism from the systemic venous system (e.g., a deep venous thrombosis) causing stroke

(1)patent foramen ovale is not conclusively a risk factor for stroke, although it is a risk factor when it is associated with an atrial septal aneurysm

(2)a patent foramen ovale is present in 20% of the general population

g.aortic arch calcifications and atheroma, particularly if 4-mm thick or mobile

h.cigarette smoking: stroke risk is proportionate to the amount of smoking; after cessation, the stroke risk reduces to nonsmoker’s level within 3 years

i.in addition to promoting atherosclerosis, cigarette smoking increases fibrinogen levels leading to a hypercoagulable state

i.dyslipidemia

i.low-density lipoprotein (LDL) 100 mg/dL, although the benefit of treating an LDL between 100–130 mg/dL in patients without other risk factors is unknown

ii.high-density lipoprotein (HDL) 40 mg/dL

iii.triglycerides 200 mg/dL

j.elevated homocysteine level: risk is proportionate to level, starting at10 mol/L

k.diabetes: a risk factor for all types of stroke, yet adequate glycemic control is known to reduce small vessel complications (e.g., retinopathy, nephropathy) but not large vessel complications

l.alcohol use: heavy use ( 4 drinks/day) has an inconsistent association with stroke that may be race dependent; low-to-moderate use (1–2 drinks/day) may reduce the risk for stroke, likely by improving the lipid profile

m.estrogen use

i.contraceptives: high-dose estrogen ( 50 g) contraceptives increase stroke risk likely because they increase blood coagulability and blood pressure; lower dose estrogen contraceptives may also increase stroke risk

(1)increased stroke risk is most marked in women 35 years old who smoke

(2)oral or injectable progesterone-only contraceptives have no apparent effect on stroke risk on their own, but may increase stroke risk in women with hypertension

ii.hormone replacement therapy: estrogen plus progesterone replacement therapy increases stroke risk in postmenopausal women

n.life-style factors: obesity, physical inactivity, diet, and psychological stress all are likely covariates with other risk factors

4.Symptoms: Focal neurological deficits, by definition 24 hours in duration for stroke and 24 hours in duration for TIA, although most TIAs last

15 minutes; speed of onset is generally considered to be acute, however rarely may develop over hours or days

a.headache: occurs in 40% of strokes; often stroke is preceded by a sentinel headache

i.headache is likely related to ischemia of the blood vessels or the meninges (Box 2.2)

Box 2.2

Only the proximal few centimeters of the named arteries are pain-sensitive.

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Table 2–1 Uses of Coumadin in Stroke Prevention

(a)dipyridamole reduces platelet aggregation by inhibiting cAMP-phosphodiesterase and by blocking adenosine reuptake

(3)ticlopidine (Ticlid): relative risk reduction for stroke 25%; used in patients who cannot tolerate aspirin, but has a high side-effect rate (diarrhea, neutropenia [1%], thrombotic thrombocytopenic purpura)

(a)reduces platelet aggregation through a poorly understood mechanism

(4)clopidogrel (Plavix): equivalent efficacy against stroke in comparison with aspirin; benefit of clopidogrel over aspirin is its superior protection against myocardial infarction

(a)reduces platelet aggregation by blocking ADP binding to adenosine receptors

(b)same side-effect profile as ticlopidine; fewer hemorrhagic side-effects in comparison with aspirin

(5)Coumadin: 67% stroke risk reduction of stroke from atrial fibrillation when international normalized ratio (INR) is 2.0–3.0 (Table 2–1)

(a)for mechanical heart valves, target INR 3.0–4.0; for bioprosthetic heart valve, target INR 2.0–3.0

(b)side effects

(i)hemorrhage (usually gastrointestinal) 7%/year with INR 3.0; hemorrhage risk increases with age 80 years old

(ii)skin necrosis, usually occurring at the initiation of Coumadin therapy (rare)

(iii)blue toe syndrome: ischemia of the extremities caused by embolization of cardiac material

(6)heparin: no proven benefit in stroke management; used commonly as a bridge to Coumadin therapy and for temporary management of unstable major artery stenosis prior to surgical or endovascular intervention

(a)side effects: heparin-induced thrombocytopenia (HIT) syndromes

(i)type I HIT: develops 5 days after starting treatment and is clinically benign; heparin causes platelet aggregation, thereby increasing blood viscosity

(ii)type II HIT: develops 1–2 weeks after starting treatment and is associated with arterial and venous thromboses; heparin-induced autoantibodies cause thrombocytopenia but also a paradoxical hypercoagulable state

v.blood pressure management: reduction to a blood pressure 140/90 mmHg or as low as is tolerated

(1)dietary modification and salt restriction, exercise, and reduction in alcohol consumption should be attempted in conjunction with medication treatment

Ischemic Stroke

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2 Vascular Diseases of the Nervous System

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(2)unclear benefit of any particular antihypertensive agent, although first-line recommendations remain angiotensin converting enzyme (ACE) inhibitors or diuretic agents; effectiveness of specific drugs may be related primarily to the degree of blood pressure reduction they achieve

(3)treat isolated systolic or diastolic hypertension

vi.dyslipidemia management: as with hypertension treatment, the particular drug may not be as important as the degree of lipid lowering that it achieves

(1)HMG-CoA reductase inhibitors/statin agents: relative-risk reduction for recurrent stroke 25%

(a)have demonstrated ability to reduce arterial plaque size over time, and may have particular benefit in stroke prophylaxis in cases where aortic plaque is a suspected source of embolization

(2)other agents (clofibrate, cholestyramine, gemfibrozil, niacin) and dietary modification generally do not lower lipid levels as much as statin agents

vii.homocysteine reduction: reduction with vitamin therapy (i.e., vitamin B1 vitamin B12 folate) has an unclear effect on recurrent stroke prophylaxis, but reduction is certainly beneficial in inherited disorders of homocysteine metabolism (see p. 72)

viii.control of hyperglycemia: no proven benefit in stroke prevention; considerable evidence exists that small-vessel disease in other organs (e.g., retinopathy, nephropathy) is reduced with strict glycemic control

ix.carotid endarterectomy (Box 2.3)

(1)in some studies, asymptomatic stenosis of 60–99% has a 55% relative risk reduction for stroke if operative mortality 3% and if the patient has a 5-year life expectancy; untreated stroke risk of asymptomatic stenosis is 1%/year

(2)symptomatic stenosis of 70–99% has a 65% relative risk reduction for stroke if operative mortality 6% and if the patient has a 5-year life expectancy

(a)untreated stroke risk of symptomatic stenosis is 13%/year

(b)benefit of surgery persists for only less than 1 year after stroke or TIA, therefore surgery is best done as soon as possible after a stroke (usually within 4–6 weeks)

(c)50–70% symptomatic stenosis may also benefit from surgery in

(i)male patients

(ii)conjunction with plaque ulceration

(iii)cases involving nonlacunar hemispheric stroke or TIA

(d)endovascular stenting appears as effective as endarterectomy, with a greater restenosis rate but fewer procedural complications

II.Subarachnoid Hemorrhage

1.Causes

a.aneurysms: account for 80% of all nontraumatic subarachnoid hemorrhage (SAH)

b.other vascular malformations: arteriovenous malformations (AVM); moyamoya disease

c.head trauma: the most common cause of SAH

d.venous or capillary bleeding into the prepontine; and/or ambient cisterns {perimesencephalic hemorrhage}; not associated with aneurysms

e.venous thrombosis

Box 2.3

There is no proven treatment for completely occluded (i.e., 100%) carotid stenosis.

2.Risk factors: as per aneurysms (see p. 77), but also

a.hypertension

b.coagulopathy/anticoagulant use

c.smoking

d.drug use, particularly cocaine and amphetamines: suspecting drug abuse as the cause of SAH does not eliminate the need to search for a vascular malformation

e.estrogen use: high-dose preparations (e.g., birth control pills) may increased SAH risk; no effect of hormone replacement therapy

3.Epidemiology: accounts for 10% of all strokes

a.exhibits a familial tendency that is likely related to an inherited predisposition to aneurysm formation

4.Symptoms: pronounced headache, nausea, and stupor focal neurological deficits; severity of nonfocal symptoms in SAH is generally greater than in intracranial hemorrhage

a.seizure at the time of SAH (5%)

b.vision loss may be due to intracranial focal injury or to simultaneous retinal hemorrhage {Terson’s hemorrhage}

c.mild nonfocal symptoms often occur with small SAH {sentinel hemorrhage}

5.Diagnostic testing (Box 2.4)

a.neuroimaging: CT to determine Fisher grade of SAH and any hydrocephalus

i.thick blood layer or clot in subarachnoid space (Fisher grade III) is associated with vasospasm

ii.intraventricular blood (Fisher grade IV) is associated with noncommunicating hydrocephalus (Box 2.5)

iii.SAH can extend into the brain parenchyma (Fisher grade 4)

iv.CT identifies only 95% of SAH cases within the first 24 hours, therefore must evaluate for nonclearing hemorrhagic cerebrospinal fluid and xanthochromia if suspicion of SAH is high (see p. 35)

(1)cerebrospinal fluid xanthochromia is present in 70% of SAH cases within 6 hours and in 90% within 12 hours of SAH, but is rarely present within 2 hours of SAH

b.angiography, either conventional or CT angiography: MRA detects only70% of aneurysms and has high false-positive rate in the MCA and ACA territories

i.angiography is negative for aneurysms in 20% of SAH cases, probably because the aneurysm is hidden by the blood clot; therefore, if the first angiogram is negative, repeat it after 2–3 weeks

(1)50% of angiography-negative SAH is perimesencephalic hemorrhage

(a)if distribution of blood is typical of perimesencephalic hemorrhage and the first angiogram is negative, do not repeat the angiogram because there is low yield and good prognosis of the condition

ii.angiography demonstrates early venous drainage through AVMs, but associated aneurysms may be hidden in the AVM nidus

6.Treatment

a.acute treatment

i.blood pressure management: with an untreated aneurysm, reduce blood pressure to premorbid levels or to a MAP 130 mmHg while keeping cerebral perfusion pressure 70 mmHg

(1)“controlled” (e.g., clipped or coiled) aneurysms allow for aggressive use of hypervolemic–hypertensive–hemodilution (“triple H”) therapy for vasospasm

Box 2.4

Fisher Scale for SAH Using CT

1–No blood detected 2–Diffuse or thin blood 3–Clot or thick layer

4–Intraparenchymal or intraventricular blood subarachnoid hemorrhage

Box 2.5

Subarachnoid hemorrhage may also cause communicating hydrocephalus by direct obstruction of arachnoid granulations.

Subarachnoid Hemorrhage

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ii.reverse coagulopathy

(1)for patients on Coumadin, use

(a)2–3 units fresh-frozen plasma; titrate to normalization of coagulation measures, which may require up to 6 units

(b)vitamin K 10 mg intramuscularly: takes 12 hours to have any effect

(2)for patients on heparin, use protamine 1 mg/100 units of heparin administered

iii.control of intracranial pressure and acute hydrocephalus: place

ventriculostomy to measure and control intracranial pressure so as to maintain cerebral perfusion pressure 70 mmHg; removal of bloody cerebrospinal fluid may also reduce the risk of vasospasm

iv.surgery

(1)timing of surgery: after aneurysmal SAH, the rebleeding rate is 20% in first week without controlling the aneurysm; the rebleeding rate for AVMs is only 6%/year

(a)early surgery (in 3 days) for aneurysmal SAH lowers the risk of rebleeding, but increases the risk of iatrogenic brain injury; generally reserved for patients exhibiting at most focal neurological deficits and lethargy

(b)late surgery (in 10 days) for aneurysmal SAH allows for stabilization of the patient’s clinical condition and reduction of tissue swelling for better surgical access; generally chosen for stuporous or comatose patients

b.preventative treatments

i.surgical treatment of unruptured aneurysms: the decision to surgically treat an unruptured aneurysm is made by comparing the cumulative

rate of aneurysm rupture against the expected surgical morbidity and mortality (typically 15%)

(1)rehemorrhage from 10-mm aneurysms: 0.05%/year unruptured; 0.5%/year ruptured

(2)rehemorrhage from 10–25-mm aneurysms: 1%/year unruptured or ruptured

(3)rehemorrhage from 25-mm aneurysms: 6%/year unruptured

ii.surgical treatment of unruptured AVMs: rupture risk is only 3%; risk is higher in AVMs that are small (due to concentrated exposure of the nidus to the high pressure of the feeding artery), that are associated with aneurysms, and that have limited venous drainage

(1)as with aneurysms, the risk of SAH must be balanced against the risk of surgical intervention, which is increased by the size of the AVM, its location in eloquent cortex, and its involvement of deep venous drainage

(2)may use endovascular treatment and/or stereotactic radiosurgery when craniotomy is not feasible, or in combination with partial surgical resection

(3)the treatment must completely destroy the AVM; residual AVM has a high risk of hemorrhage and can regrow

iii.reduction of hypertension, including isolated systolic or diastolic hypertension

iv.avoid use of anticoagulation but not necessarily antiplatelet agents

7.Complications of SAH

a.vasospasm: a focal arterial constriction possibly related to a loss of vasodilatory substances (e.g., nitric oxide, which is bound by hemoglobin), the release of vasoconstrictive compounds (e.g., endothelins, prostaglandins), and/or a proliferative vascular reaction

i.period of highest risk is 4–7 days post-SAH, but vasospasm may occur up to 3 weeks post-SAH

ii.symptomatic effects of vasospasm may be focal or diffuse (i.e., encephalopathy-like)

iii.diagnostic testing: screen patients for vasospasm with daily transcranial Doppler ultrasonography to detect increased flow velocities in major arteries

(1)ultrasound flow velocities are artificially increased by a low pCO2 or hematocrit

(2)confirm ultrasonographic findings as vasospasm with cerebral angiography

iv.treatment/prophylaxis

(1)nimodipine 60 mg PO q4h for 21 days beginning immediately after SAH

(a)may have direct protective effect on the brain because it does not have much effect on vascular caliber

(2)hypervolemic–hypertensive–hemodilution (“triple H”) therapy has no proven benefit, but is standard-of-care

(3)intraarterial papaverine or angioplasty of the vasospastic artery segments has no established benefit

b.hydrocephalus: treat with intraventricular shunt; intraventricular thrombolytics may be used with clipped aneurysms to clear the subarachnoid blood clot

c.hyponatremia: caused by natriuresis from excessive sympathetic activity (i.e., cerebral salt wasting (see p. 16)), rarely by syndrome of inappropriate antidiuretic hormone (SIADH)

d.cardiac arrhythmias and ischemic-like EKG changes due to increased sympathetic activity

e.seizures: prophylaxis is commonly used in the acute setting, but there is no evidence that it prevents the development of epilepsy

III. Intracranial Hemorrhage

1.Pathophysiology: hemorrhage within the brain parenchyma that separates tissue planes, forming a well-demarcated hematoma; intracranial hemorrhages (ICHs) are located more often in the putamen than in the cortex, thalamus, cerebellum, or pons

a.ICHs from large vessel disease are rare and generally are from rupture of an AVM or extension of SAH into the brain parenchyma (Fisher grade 4 SAH)

b.ICH from small vessel disease is usually related to

i.hypertensive angiopathy—breakdown of the blood–brain barrier in arterioles of chronic hypertensive patients leads to deposition of plasma proteins in the tunica media, inflammatory degeneration of the smooth muscle, and endothelial hypertrophy {lipohyalinosis}; affected arterioles usually also exhibit atherosclerotic changes

(1)many arteriolar microaneurysms {Charcot–Bouchard aneurysms} are likely coils of small arterioles, but aneurysmal dilation of severely hyalinized arterioles do occur; however, ICH does not necessarily occur by rupture of a microaneurysm

ii.amyloid angiopathy—develops when fibrillary proteins form a -pleated sheet conformation that deposits in the walls of arterioles as amyloid, causing wall thickening and lumen narrowing; amyloid deposits can extend into the surrounding perivascular tissue, resembling senile plaques of Alzheimer’s disease

(1)histology: similar to lipohyalinosis except that amyloid angiopathy is congophilic (i.e., exhibits apple green birefringence after Congo red staining) whereas lipohyalinosis is eosinophilic (i.e., stains with hematoxylin)

(2)ICH from amyloid angiopathy often extends into a SAH because of the cortical location of the ICH (Box 2.6)

Box 2.6

Other Symptoms of Amyloidosis

Dementia, either from multiple infarcts or from coincident Alzheimer’s disease

Peripheral neuropathy (e.g., carpel tunnel syndrome)

Renal failure, heart failure, purpura, macroglossia

Intracranial Hemorrhage

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