CNS/PNS cells

Astrocytes
o Star shaped glial cells in brain and spinal cord
o

Provides support and maintains blood brain barrier

Principal role in repair/scarring of brain and spinal cord after injury

Expresses the filament glial fibrillary acidic protein (GFAP). Note:

ependymal cells also express GFAP

Ependymal cells
o

Form the inner epithelial lining of cerebral ventricles and central canal of
spinal cord

Involved in production of CSF

Microglia
o

CNS phagocytes

Origin is mesodermal (all other CNS/PNS support cell types originate from
ectoderm)

Current evidence suggests that chronic activation of microglia can accelerate

the formation of neurofibrillary tangles
[1] [2]

Oligodendroglia
o Forms myelin around multiple CNS axons
o

These are the major types of glial cells found in white matter

Oligodendroglia are destroyed in multiple sclerosis, cerebral palsy, and

progressive multifocal leukoencephalopathy (PML).
PML:
- Demyelinating disease caused by JC virus (JCV), a type of human
polyomavirus, in immunocompromised (e.g., AIDS) patients limb
weakness, problems with speech
- JC virus: icosahedral capsid, nonenveloped, circular dsDNA

Schwann Cells
o

While one oligodendrocyte myelinates multiple axons in the CNS, one

Schwann cell can only myelinate one axon in the peripheral nervous system.

Derived from neural crest cells

Aids in axonal regeneration

Clinical correlation: Schwann cells can form acoustic neuromas

(schwannomas). Usually unilateral and located at the junction of the
cerebellum and the pons. Associated with cerebellopontine angle syndrome.
[3]

~90% of bilateral schwannomas are associated with neurofibromatosis type

2 (NF2), a hereditary condition

Astrocytes in red amongst neuronal cells

Oligodendrocyte with multiple myelin extensions

Peripheral Nerve Layers

Endoneurium covers a single nerve fiber

Perineurium covers a fascicle of nerve fibers

Epineurium covers the entire nerve which consists of fascicles and blood vessels

Nerve structure

Nerve structure

Location of Neurotransmitter Synthesis

Dopamine ventral tegmentum, substantia nigra, and hypothalamic arcuate nucleus

5HT (serotonin) raphe nucleus

NE (norepinephrine) locus ceruleus

Ach (acetylcholine) basal nucleus of Meyner

Blood Brain Barrier

Blood brain barrier (BBB) is formed by:

o 1) Tight junctions that form between nonfenestrated capillary endothelial
cells
o

2) Basement membrane

3) CNS astrocyte processes

Nonpolar/lipid-soluble particles (CO2, O2, water, EtOH) cross BBB rapidly by

diffusion

Glucose and amino acids cross BBB slowly and require carrier mediated transport

Hypothalamus

Regulate adenohypophysis (via release factors) and neurohypophysis (via direct

axon transport)
Hypothalamus functions include:
o

1) Autonomic regulation. Anterior hypothalamus regulates the

parasympathetic system; whereas, the posterior hypothalamus regulates the
sympathetic system.

2) Circadian rhythms via suprachiasmatic nucleus. The Reticular Activating

System (RAS) is a brainstem structure which relays through the
hypothalamus and regulates sleep and arousal

3) Temperature regulation. When patient is hot, the anterior hypothalamus

stimulates cooling. When patient is cold, the posterior hypothalamus
regulates heat production.

4) Sexual desires and emotions. Input is also provided by the amygdala.

5) Hunger and thirst/satiety/water homeostasis. Supraoptic nucleus secretes

anti-diuretic hormone and stimulates thirst in response to increased
osmolarity

Hypothalamus

Cerebral cortex functions

Frontal Lobe
o Primary motor cortex (4) and pre-motor cortex (6): responsible for
movement of muscles in contralateral half of body. Lesion results in
contralateral spastic hemiparesis.
o

Broca's area (44, 45): located in posterior part of the dominant frontal lobe,
specifically within the inferior frontal gyrus. Responsible for motor speech.

Lesion here results in expressive (motor) aphasia: cannot articulate speech or

write normally, but can comprehend written and spoken language.
o

Frontal association areas responsible for orientation, attention and judgment.

Lesion here results in personality changes and deficits in orientation,
judgment, and mood.

Parietal Lobe
o

Principal sensory areas (3, 1, 2)

Spatial neglect syndrome: lesion in right parietal lobe results in agnosia of

contralateral side of the world

Temporal Lobe
o

Primary auditory cortex (41,42)

Wernickes area (22) superior temporal gyrus: lesion here results in sensory
(fluent/receptive) aphasia with poor comprehension

Occipital Lobe
o

Principal visual cortex (17)

Broca's area inferior frontal gyrus

Circle of Willis

Anterior cerebral artery

o Supplies medial surface of brain
o

Olfactory bulb and tract

Occlusion in ACA (anterior cerebral artery) may result in:

paralysis/sensory loss of contralateral foot and leg, gait apraxia,
urinary incontinence

Middle cerebral artery

o

Supplies lateral surface of brain

Supplies Broca and Wernicke areas as well as motor/sensory

cortex of the trunk-arm-face

Occlusion in MCA (middle cerebral artery) may result in:

paralysis/sensory loss of contralateral face and arm, Brocas and
Wernickes aphasia, contralateral neglect syndrome

Anterior communicating artery

o

Most common location of berry aneurysms in the Circle of Willis

Aneurysm here may result in visual field defects such as

bitemporal hemianopsia
[1]

Posterior communicating artery: aneurysm may result in CN III palsy

Bitemporal hemianopsia

Circle of Willis

Spinal Cord

Gray matter consists of neuronal cell bodies

o Divided into dorsal horn, ventral horn, and lateral horn

White matter consists of neuronal fibers

C1-C7 nerves: exit via intervertebral foramina at the level above the corresponding
vertebra

Spinal nerve C8 exits below vertebra C7. T1 through L5 exit at the level below the
corresponding vertebra.

Thoracic level: T1 - T12 (12 nerves)

Lumbar level: L1 L5 (5 nerves)

Sacral level: S1 - S5 (5 nerves)

Vertebral disk herniation is most common at the L5-S1 level

Spinal cord extends to L1-L2 level in adults

o

The cauda equina consists of dorsal and ventral nerve roots of spinal nerves L2
coccygeal 1
o

The end of the spinal cord is referred to as the conus medullaris

These nerves travel in subarachnoid space below the conus medullaris

Subarachnoid space extends to S2 level in adults

Basal ganglia

Consists of the striatum, globus pallidus, subthalamic nuclei, and substantia nigra
o Corpus striatum = globus pallidus + putamen + caudate nucleus
o

Lentiform nucleus = globus pallidus + putamen

Striatum (neostriatum; caudatoputamen) = caudate nucleus + putamen

Modulates thalamic outflow to the motor cortex (serves to plan and execute smooth
movements)

Many of the synaptic connections are inhibitory and use GABA (gamma
aminobutyric acid) as the inhibitory neurotransmitter

Connection between striatum and substantia nigra use dopamine as their

neurotransmitter

Lesion of globus pallidus

o

Results in loss of postural support

Lesion of subthalamic nucleus

o

Leads to loss of inhibition

Results in wild, flinging movements (hemiballismus)

Lesion of striatum
o

Leads to loss of inhibition

Results in quick, continuous, uncontrollable movements

Seen in Huntingtons disease (chorea)

Lesion of substantia nigra

o

Dopamine is produced in the SN. Because dopamine is an excitatory

neurotransmitter, destruction of these neurons unopposed inhibition of
the pathways from striatum to globus pallidus

Occurs in Parkinsons disease

Results in lead pipe rigidity, tremor, and reduced voluntary movement due to
destruction of dopaminergic neurons

Major tracts of spinal cord

Dorsal column-medial lemniscus pathway

o Mediates tactile discrimination, vibration sensation, form
recognition and joint/muscle sensation (proprioception)

Spinothalamic pathway: comprised of the lateral spinothalamic tract and

the ventral (anterior) spinothalamic tract

Lateral spinothalamic tract mediates pain and temperature

sensation

Ventral (anterior) spinothalamic tract mediates crude

touch/pressure

Lateral corticospinal tract:

o

Mediates descending voluntary skilled motor activity of ipsilateral

limbs (ipsilateral because the motor fibers in the lateral
corticospinal tract are distal to the pyramidal decussation in the
caudal medulla)

Spinal tracts

Cranial Nerves

CN I (Olfactory)
o Mediates sense of smell (olfaction)

CN II (Optic)
o

Mediates sense of sight (vision)

Formed by axons of ganglion cells in the retina, CN II mediates vision,

afferent limb of pupillary light reflex (efferent limb = CN III)

Pupillary light reflex:

Light rods/cones bipolar cells retinal ganglion cells, whose axons
form CN II.
CN II projects to the pretectal nuclei (midbrain), which send bilateral
projections to the Edinger-Westphal (EW) nucleus (also known as the
accessory motor nucleus of CN III).
Preganglionic parasympathetic fibers (from EW nucleus) synapse in the
ciliary ganglion postganglionic parasympathetics stimulate the sphincter
pupillae to contract miosis.
Note: The key to understanding the indirect light reflex: each pretectal
nucleus projects to both right and left Edinger-Westphal nuclei.
Example: shine light in right eye miosis of right pupil (direct light
reflex) and miosis of left pupil (indirect light reflex).

Lesion of optic radiations or visual cortex cortical blindness: blindness +

intact pupil reflexes (because neither the optic radiation nor the visual cortex
are involved in the pupillary light reflex)

CN III (Oculomotor)
o

Innervates four extraocular muscles which control eyeball movement:

- Medial rectus: adductssimultaneous stimulation of both medial rectus
muscles convergence
- Superior rectus: elevates, adducts, intorts
- Inferior rectus: depresses, adducts, extorts
- Inferior oblique: elevates, abducts, extorts
- CN III palsy "down and out" pupil, external strabismus, and diplopia
when looking toward the lesioned side

Contraction of levator palpebrae superioris elevates upper eyelidlesion

ptosis (droopy upper eyelid)

Preganglionic parasympathetic fibers from Edinger-Westphal nucleus in

midbrain travel with CN III
Synapse in ciliary ganglion
Postganglionic parasympathetic fibers contraction of ciliary muscle
(accomodation) and sphincter pupillae (miosis)

Contraction of ciliary muscle accommodation (increased refractive

power of lens for near-vision)lesion of CN III cycloplegia (paralysis of
accommodation) blurred vision

Contraction of sphincter pupillae miosis (pupil constriction)lesion of

CN III fixed, dilated pupil.

Note:
Sphincter pupillae fibers are often first affected with:
1) Uncal (transtentorial) herniation
2) Aneurysms of the posterior communicating or carotid arteries
In contrast, diabetes mellitus diabetic CN III palsy, which spares the
sphincter pupillae and damages fibers located more centrally within the
nerve.

CN IV (Trochlear)
o

The contralateral trochlear nucleus in the caudal midbrain gives rise to CN

IV, which decussates under the superior medullary velum and emerges from
the dorsal surface of the midbrain to innervate the superior oblique muscle
NOTE: CN IV is the only cranial nerve to emerge from the dorsal aspect of
the brainstem.
Also, lesions of the superior medullary velum may damage the underlying
CN IV decussation bilateral CN IV palsy

Actions of the superior oblique on the globe of the eye:

- Depression
- Abduction (ie, anterior aspect of eye moves laterally)
- Intortion (ie, superior aspect of eye moves medially)

Lesion of CN IV paralysis of superior oblique extorsion (top of eye

moves laterally), which causes two things:
1) Vertical diplopia which is worse with downward gaze
2) Compensatory head tilting (tilt chin toward affected side, or equivalently,
tilt top of head away from affected side)
For example:
Lesion:
- If there is a lesion of the left CN IV paralysis of the left superior oblique
extorsion of left eye causes overlap of vertical axes of the visual fields,
resulting in vertical diplopia.
Compensation:
- Tilting the chin to the left (toward the affected side)or equivalently,
tilting the top of the head to the right (away from the affected side)causes
a compensatory intorsion of right eye binocular alignment

Superior oblique = muscle most involved in downward gaze of an adducted

eye the integrity of CN IV and the superior oblique are tested by having
the patient adduct, then depress the eye.
Lesion of CN IV paralysis of superior oblique weakness looking down
when eyes are adducted trouble reading the newspaper or walking
downstairs. Such patients also experience double vision when performing
these tasks due to vertical diplopia with downward gaze (see above).

CN V (Trigeminal) has 3 divisions: opthalmic (V1), maxillary (V2) and mandibular

(V3)
o

V1, V2 and V3 provide sensory innervation to the face and oral/nasal mucosa
lesion hemianesthesia

V1 = afferent limb of corneal reflex (CN VII = efferent limb of corneal

reflex)lesion loss of corneal reflex

V3 provides motor innervation to muscles of mastication (masseter,

temporalis, medial pterygoid, and lateral pterygoid) as well as to the tensor
tympani and tensor veli palatini:
Masseter, temporalis, and medial pterygoid raise/close the jaw
(mandible).
Lateral pterygoid Lowers/opens the jaw (mandible) and causes deviation
of the mandible to the opposite side.
Lesion of V3 flaccid paralysis of muscles of mastication jaw deviates
toward the lesioned side due to the unopposed action of the intact
contralateral lateral pterygoid muscle.
Tensor tympani contracts in response to loud sounds, tensing the
tympanic membrane (a protective dampening effect)
Lesion of V3 paralysis of tensor tympani hypoacusis (versus
hyperacusis due to a lesion of stapedius, which is innervated by CN VII)
Tensor veli palatini tenses and stabilizes the soft palate so that levator
veli palatini (innervated by CN X) can elevate the soft palate
Lesion of V3 paralysis of tensor veli palatini less robust soft palate
elevation on the lesioned side

Tic douloureux (trigeminal neuralgia, prosopalgia) = recurrent episodes of

stabbing pain on one side of the face within one or more of the trigeminal
nerve distributions (V1, V2, V3)

CN VI (Abducens)
o

Innervates lateral rectus muscle. Lesion causes inability to abduct eye, so

eye is medially directed (when eyes do not align: a medial pupil deviation is

called esotropia or internal strabismus; a lateral pupil deviation is called

exotropia or external strabismus)

CN VII (Facial)
o

Exits the brainstem at the cerebellopontine angle and courses alongside CN

VIII into the internal auditory meatus
CN VII traverses the facial canal
Exits skull through stylomastoid foramen
Note: An acoustic neuroma (which is a Schwannoma of the Vestibular
Division of CN VIII) may compress and damage CN VII

Innervates the muscles of facial expressioneg, frontalis, orbicularis oculi,

buccinator, orbicularis oris, platysma, etc.
Lower motor neuron (LMN) lesion of CN VII
- Ipsilateral flaccid paralysis of upper and lower facial muscles of expression
(Bell's palsynote: bilateral Bell's palsy can be seen in second stage Lyme
disease)
- Loss of efferent limb of corneal blink reflex (afferent limb = V1)
possible corneal ulceration, blindness
UMN lesion of CN VII (supranuclear facial palsy) contralateral paresis of
lower facial muscles of expression only (upper face is spared, e.g., can
wrinkle forehead)

Innervates the stapedius muscle

- Paralysis of stapedius hyperacusis

Mediates taste sensation from the anterior two-thirds of the tongue:

- Taste pathway: taste buds chorda tympani geniculate ganglion within
the temporal bone nucleus of solitary tract (carries taste from CN VII, IX,
X) VPM thalamus gustatory cortex of parietal lobe
- Lesion ageusia of anterior two-thirds of tongue

Mediates salivation and lacrimation:

Superior salivatory nucleus
1. Preganglionic parasympathetics travel in the chorda tympani, pass
through the geniculate ganglion, synapse in submandibular ganglion
postganglionic parasympathetics innervate submandibular and sublingual
salivary glands.
2. Preganglionic parasympathetics travel in the greater petrosal nerve, pass
through the geniculate ganglion, synapse in pterygopalatine ganglion
postganglionic parasympathetics innervate lacrimal glands.

The five motor branches of the facial nerve passing through the parotid gland are
(Use the mnemonic "To Zanzibar By Motor Car"):
o

Temporal

Zygomatic

Buccal

Marginal mandibular

Cervical

CN VIII (Vestibulocochlear)
o

"Crocodile tears" syndrome: lesion of salivatory preganglionic

parasympathetics regenerating fibers may be misdirected to the
pterygopalatine ganglion lacrimation during eating

Mediates hearing and balance

CN IX (Glossopharyngeal)
o

Mediates taste and general sensation of the posterior 1/3rd tongue and
mucosa of the oropharynx. Also monitors input from carotid body and sinus
chemo-baroreceptors. The only pharyngeal muscle innervated by CN IX is
the stylopharyngeus.

Lesion causes loss of afferent limb of gag reflex and loss of taste and general
sensation from posterior third of tongue

CN X (Vagus)
o

Mediates speech and swallowing. Lesion results in paralysis of pharynx and

larynx, deviation of uvula OPPOSITE to side of injured nerve. It is also the
efferent limb of the gag reflex.

Monitors inputs from aortic arch chemo-baroreceptor

CN XI (Accessory)
o

CN XI innervates 2 muscles:
1) sternocleidomastoid
2) trapezius

SCM (sternocleidomastoid) laterally flexes the head/neck and rotates

head/neck to opposite side; both SCMs working together flex the head/neck
(i.e., move head to look straight down by tilting chin toward chest).
- unilateral lesion of CN XI ability to turn head to opposite side of
injured nerve.

- bilateral lesion of CN XI ability to look straight down by tilting chin

toward chest.
o

Trapezius upward rotation, retraction, and elevation of scapula (i.e., shrug

shoulder upward).
- lesion of CN XI ability to shrug ipsilateral shoulder.

CN XII (Hypoglossal)
o

Innervates intrinsic and extrinsic tongue muscle (except for palatoglossus,

which is innervated by CN X). Lesion causes deviation of tongue to SAME
side of injured nerve.

CN V sensory innervation

CN VII motor branches. 1)Temporal 2)Zygomatic 3)Buccal 4)Marginal Mandibular

5)Cervical

Congenital Nervous System Disorders

Neural tube defects

Associated with increased alpha fetoprotein in amniotic fluid

Associated with maternal folic acid deficiency

Spina bifida failure of posterior vertebral arches to close. Several forms which
include:
o

1) Meningocele herniated membranes consisting of only meninges

2) Meningomyelocele herniated meninges and spinal cord

3) Spinal bifida occulta vertebral arches do not form in lumbar area but
spinal cord is normal. No symptoms, may have a lumbar dimple, lipoma, or
tuft of hair on exam.

TORCHeS infections:
o

Toxoplasma
Rubella
CMV
Herpes simplex, HIV
Syphilis (Treponema pallidum)

Associated symptoms include microcephaly, jaundice or

hepatosplenomegaly.

Arnold-Chiari malformation
o

Downward displacement of cerebellar tonsils and medulla through the

foramen magnum

Results in obstruction of CSF (cerebrospinal fluid) outflow tract and causes

hydrocephalus. May present with headaches, visual changes, seizures or
confusion.

Increased incidence of coexisting thoracolumbar meningomyelocele or

syringomyelia (most common at C8-T1)

Fetal alcohol syndrome: most common cause of mental retardation (affecting 1 4.8 per 1000 children born in the US) versus:
- Down syndrome: most common genetic cause of mental retardation
- Fragile X syndrome: most common inherited cause of mental retardation
o

Mental retardation due to CNS (central nervous system) damage:

- prenatal alcohol exposure (especially during the first trimester) may disrupt
crucial developmental pathways, including the retinoic acid and Hedgehog
pathways

Growth retardation
- small body size

- microcephaly
- midface hypoplasia
o

Midface abnormalities:
1) short palpebral fissures
2) epicanthal folds
3) long philtrum
4) thin upper lip

Heart defects:
- VSD (ventricular septal defect)
- ASD (atrial septal defect)

Meningomyelocele

Fetal Alcohol Syndrome

Phakomatoses (Neurocutaneous Syndromes)

Phakomatosis incidence: NF (neurofibromatosis) > TS (tuberous sclerosis) > SWS

(Sturge-Weber syndrome)
o Inheritance:
- NF: autosomal dominant with variable expression
- TS: autosomal dominant
- SWS: sometimes due to somatic mosaicism, other times due to sporadic
mutation

NF type 1: associated with mutation of a tumor suppressor gene called

neurofibromin (which inhibits the p21 ras oncoprotein) on chromosome 17
overactivity of ras may cause some of the manifestations of NF type 1

NF type 2: associated with mutation in a tumor suppressor gene called

merlin (a critical regulator of contact-dependent inhibition of proliferation)
on chromosome 22

TS: associated with mutations of two genes:

- TSC1 gene (chromosome 9) codes for a protein called hamartin, which
regulates the cell-cycle, neuronal synapse formation and axon development
- TSC2 gene (chromosome 16) codes for a protein called tuberin, which
has GTPase-activating activity and regulates protein translation, growth and
cell proliferation
- hamartin and tuberin form heterodimers

NF (neurofibromatosis) type 1: diagnosis is made if a patient has 2 of the "cannot

fail to be first" criteria "CA NN OT FAI L 2 B 1st":
o

CA 6 CAf au lait (coffee-colored) macules (5mm in kids; 15mm in

adults)

NN 2 Neurofibromas (flesh-colored skin nodules secondary to Schwann

cell proliferation) or 1 plexiform neurofibroma

OT OpTic gliomas

FAI Freckling: Axillary or Inguinal

L 2 2 Lisch nodules (pigmented iris hamartomas)

B Bone abnormality, for example:

- kyphoscoliosis
- tibial dysplasia bowing of tibia
- sphenoid dysplasia

1st 1 1st degree relative with neurofibromatosis type 1

Malignancies associated with NF type 1 include:

o

pheochromocytoma

Wilm's tumor

juvenile CML (chronic myelogenous leukemia)

Note: pheochromocytoma and Wilm's tumor are both associated with

hypertension

NF (neurofibromatosis) type 2: diagnosis is made if a patient has bilateral acoustic

neuromas (benign schwannomas of vestibular division of CN8), which may present
as sensorineural hearing loss, tinnitus, and vestibular disorientation.
o

Besides bilateral acoustic neuromas, other findings associated with

neurofibromatosis type 2 include:
- juvenile cataracts in ~80% of patients
- schwannomas e.g., unilateral acoustic neuromas, spinal schwannomas
- meningiomas
- gliomas

Like NF type 1, patients with NF type 2 may have:

- caf au lait (coffee-colored) macules
- cutaneous neurofibromas

TS (tuberous sclerosis): use the mnemonic "AASS RRRASH":

o

Ash Leaf Spots: Hypopigmented spots often found on the skin of TS

patients

Angiofibromas (adenoma sebaceum) of the face: reddish brown papules

on the nose and cheeks in a butterfly distribution

Shagreen patches: rough papules with orange-peel consistency usually on

the trunk
- best identified with a Wood's lamp (UV-A light)

Seizures (infantile spasms)

Retardation (mental)

Retinal lesions:
- mulberry tumors
- phakomas: round flat gray lesions located peripherally in the retina

Rhabdomyomas in the heart may cause CHF (congestive heart failure)

- a cardiac rhabdomyoma in a young child is highly suspicious (nearly 100%
specific) for tuberous sclerosis

Angiomyolipomas of the kidney: hamartomatous lesions

Subependymal astrocyte proliferation in the brain: hamartomatous

lesions that look like "candlestick dripping" in cerebral ventricles
- multinucleated atypical astrocytes may also form tubers (small white
nodules) in cerebral cortex and periventricular locations

Hamartomas

Sturge-Weber Syndrome (encephalotrigeminal angiomatosis): rare congenital

syndrome characterized by:

1) Neurologic deterioration
2) Facial port-wine stain nevus flammeus "birthmark" in the trigeminal nerve
distribution
3) Leptomeningeal hemangiomas
4) Buphthalmos (markedly enlarged eye) [1]
o

Children develop progressive neurologic deterioration:

- Seizures
- Mental retardation
- Hemiparesis
- Hemisensory deficit

Port-wine stain nevus flammeus "birthmark":

- Macular vascular lesion (congenital unilateral capillary or cavernous
hemangioma) on the face in the dermatomal distribution of cranial nerve V
usually the V1 or V2 dermatomal distribution
- Does not blanch with pressure

Some patients have an ipsilateral arteriovenous malformation of pia mater

vessels (ipsilateral leptomeningeal angioma) overlying occipital and
parietal lobes

Skull X-ray of patients after 2 years of age:

- Gyriform "tramline" intracranial calcifications

Children often suffer from visual disturbances (eg, hemianopia) and often
present with buphthalmos (markedly enlarged eye):
- Congenital glaucoma retained aqueous humor buphthalmos
(markedly enlarged eye)

Caf au lait macules in a patient with neurofibromatosis.

Image credit: www.GeneTests.org
Image copyright: University of Washington, Seattle

Neurofibromas in a patient with neurofibromatosis.

Image credit: www.GeneTests.org
Image copyright: University of Washington, Seattle

Cerebrovascular Infarction

Characterized by liquefactive necrosis leading to cyst formation. By contrast,

coagulative necrosis occurs after a myocardial infarction.
Atherosclerosis disease can cause thrombosis of cerebral vessels infarct occurs
due to decreased blood supply to the brain

The middle cerebral artery and carotid bifurcations are the most common sites of
thrombotic occlusions

Alternatively, emboli can cause infarcts. The middle cerebral artery is the most
common site of embolic occlusion. Occlusion of the middle cerebral artery results
in contralateral paralysis, motor and sensory defects.

Lacunar strokes are pure motor (internal capsule) or pure sensory strokes (thalamus)
from obstruction of small vessels

Cerebrovascular Hemorrhages

Intracerebral hemorrhage: bleeding into brain parenchyma

o Intracerebral hemorrhage can result from:
- Hypertension (acute hypertension=most common cause)
- Tumor encroachment on vessels
- Cerebral amyloid angiopathy
o

Chronic hypertension small vessel vasculopathy predisposes to the

formation of Charcot-Bouchard aneurysms, which may rupture due to the
increased wall stress caused by hypertension intracerebral hemorrhage

Note:
Charcot-Bouchard aneurysms = microaneurysms that occur in the small
perforating arteries of the brainfor example:
- Lenticulostriate vessels (most common site)
- Thalamoperforator vessels
- Paramedian branches of the basilar artery
- Superior cerebellar arteries
- Anterior inferior cerebellar arteries
o

Most common sites of hypertensive bleeds in the CNS (in descending order
of frequency):
1) Basal ganglia is most common site50-60% of these basal ganglia
bleeds originate in the putamen
2) Thalamus
3) Pons
4) Cerebellum

Cerebral amyloid angiopathy involves the same amyloid protein found in

Alzheimers disease:
- Deposition of -amyloid protein in cortical vessels weakening of vessel
walls risk for lobar (eg, frontal, temporal, parietal, occipital cortex)
intracerebral hemorrhage
- Primary etiology of lobar hemorrhage is usually cerebral amyloid
angiopathy, not hypertension
[1] [2]

Subarachnoid hemorrhage: bleeding into subarachnoid space

o Xanthochromia (blonde color) of the CSF after a subarachnoid hemorrhage
is caused by oxyhemoglobin and bilirubin
o

Frequently caused by berry aneurysm (also known as a "saccular" aneurysm)

of the circle of Willis (patients complain of a sudden worst headache)
Berry aneurysm rupture subarachnoid hemorrhage
Much more common in the anterior segment of the circle of Willis
Highly predictable spatial distribution:
- 40% at junction of anterior communicating artery and anterior cerebral
artery
- 34% at bifurcation of MCA
- 20% at junction of ICA and posterior communicating artery
- 4% at bifurcation of basilar artery
Commonly seen in:
- Coarctation of the aorta

- polycystic kidney disease

- Marfan syndrome
- Ehlers-Danlos syndrome

Can be associated with arteriovenous malformations or trauma

Potential complication: vasospasm. May be prevented by calcium channel

blockers.

General note:
Any increase in intracranial pressure is initially compensated by shifting of
cerebrospinal fluid into spinal subarachnoid space

Head injuries

Can result from penetrating wounds or nonpenetrating injuries (contusions)

Epidural hematoma:
o

Associated with skull fracture

Arterial hemorrhage from laceration of middle meningeal artery near the

temporal bone

Characterized by lucid interval (brief period of improvement) followed by

rapid signs of cerebral compression

Does not bleed into brain substance so amenable to emergent surgical

evacuation to decrease intracranial pressure

CT scan shows a highly attenuating convex ("lenticular") shaped mass

overlying the brain. Epidural hematomas are also less likely to cross suture
lines than subdural hematomas.

Subdural hematoma:
o

Associated with venous bleeding from torn bridging veins

More common in victims of abuse (e.g., shaken baby syndrome, elderly

abuse) and in patients with atrophic brains prone to falls (e.g., alcoholics,
elderly)

Characterized by gradual signs of cerebral compression than may manifest

in hours to days. In this scenario, an elderly person can have progressive
confusion which goes unnoticed until a coma occurs.

CT scan shows a crescent shaped (concave) hematoma which is less dense

than an epidural hematoma due to dilution of the blood by CSF. Subdural

hematomas are also more likely to cross suture lines than epidural
hematomas.
Add 2 quiz questions

Epidural Hematoma note the biconvex shape

Subdural Hematoma note the crescent shape

Nonviral CNS Infections

There are no lymphatics in the CNS

The most common infection entry is through hematogenous spread

Pyogenic meningitis can present with fever, headache, photophobia and nuchal
rigidity
o

CSF profile: numerous neutrophils, glucose, protein

Etiology is clued by patients age: neonates and infants group B

streptococcus, E. coli, Listeria

Older infants young adults : Streptococcus pneumoniae and Neisseria

meningitidis

Older adults elderly: Streptococcus pneumoniae and gram negative rods

Neisseria meningitidis can result in Waterhouse Friderichsen syndrome

Cerebral abscess can result from:

o

Direct extension from paranasal sinuses or middle ear (most common)

infection

Infective endocarditis

Bronchopulmonary infections

Other nonviral CNS infections

o

1) Tuberculosis with associated meningitis, hydrocephalus, vasculitis or

infarction (>50% of patients). CT scan shows dilatation of ventricles with
marked enhancement of basal cistern and meninges.

2) Fungal Cryptococcus, Aspergillus, Histoplasma, and Coccidioides

3) Toxoplasmosis Toxoplasma gondii parasitic infection is more common

in HIV or immunocompromised patients.

A. In neonates, transmitted transplacentally from mother. Results in

periventricular calcifications and hydrocephalus

B. In adults, ingestion of food contaminated by cat feces

4) Prion disease (e.g. CreutzfeldtJakob disease)

A. Infectious protein particles devoid of DNA or RNA

B. Characterized by spongiform encephalopathy, which describes small

cysts in CNS gray matter with striking absence of inflammatory response

C. Long incubation period, but progresses rapidly once symptoms appear.

Symptoms include subtle changes in memory and behavior followed by
dementia, confusion, and ataxia.

D. Risk factors include ingestion of brain matter, corneal transplantation,

and infection with mad cow disease

Viral infections

Can be limited to meninges (meningitis), involve entire brain (encephalitis), or both

(meningoencephalitis)
Viral meningitis CSF profile: lymphocytes, moderate protein, normal glucose

Examples of viral infection:

Arbovirus encephalitides (St. Louis, eastern equine, western equine): mosquito

vector

Herpes simplex encephalitis: seen in teenagers and young adults, localized to

temporal and frontal lobe

Rabies: can be aborted by active immunization before the onset of clinical

manifestations. Characterized by formation of Negri bodies, which are eosinophilic
intracytoplasmic inclusions commonly found in the hippocampus and Purkinje cells
of cerebellum.

Cytomegalovirus: common in immunosuppressed patients. Characterized by

eosinophilic inclusions in both nucleus and cytoplasm. Encephalomyelitis with
associated kidney, liver, or lung lesions. In infants, periventricular calcifications
with chorioretinitis, hepatosplenomegaly, and mental retardation are common.

HIV encephalitis: characterized by diffuse myelin damage (spongy myelinopathy

with gliosis), neuronal loss, vascular damage, lymphocytic infiltrates in white
matter, and multinucleated giant cells (formed from fusing of membranes of
infected macrophages). Measurement of magnetization transfer in MR imaging may
help distinguish HIV encephalitis from progressive multifocal leukoencephalopathy.
o

May manifest as AIDS dementia complex: personality changes, depression,

difficulty with balance

Poliomyelitis: degeneration and necrosis of anterior horn cells of spinal cord

Slow progression viral infections: two types of viral CNS infection that have a slow
clinical progression
o

1) Subacute sclerosing panencephalitis

Persistent infection with an altered measles virus

Infected during infancy but will not manifest with neurological symptoms
until early teenage years, usually fatal

Characteristic: CSF contains oligoclonal immunoglobulins against viral

proteins

2) Progressive multifocal leukoencephalopathy

Caused by JC polyoma type of papovavirus, which infects oligodendrocytes

(inclusion bodies may be seen on microscopy) and astrocytes.

Damaged oligodendrocytes multifocal demyelination in brain

Associated with leukemia, lymphoma, or HIV

Multiple Sclerosis

Epidemiology
o More common in women
o

Pregnancy may increase susceptibility to relapse

More common in ages 20-30

Association with HLA haplotypes A3, B7, DR2, DW2

Incidence directly proportional to geographic distance from the equator.

[1]

Morphologic changes
o Confined to CNS
o

Peripheral nerves not affected

Depletion of myelin producing oligodendrocytes

Multiple foci of demyelination plaques can be found in the cortex, spinal

cord, optic nerve, paraventricular areas

Clinical Manifestations
o

Variable course

Characterized by exacerbations with long, asymptomatic remissions

Early findings: lower extremity weakness, visual disturbance with

retrobulbar pain, and loss of bladder control
- Visual disturbance: Unilateral visual impairment is usually the initial
manifestation (optic neuritis)
- Internuclear ophthalmoplegia due to interruption of the medial longitudinal
fasciculus

Classic Charcot triad: nystagmus, intention tremor, and scanning speech

Under electrophoresis, CSF immunoglobulins often manifest as multiple

oligoclonal bands

LHermittes sign: shock-like feeling on neck flexion

Symptoms may worsen with heat (e.g., bath, warm weather)

Treatment:
o

-Interferon

Immunosuppressant therapy

Corticosteroids for acute exacerbations

Symptomatic treatment:
- Baclofen or other anti-spasmodics
- Pain management

Relatively new therapeutic options:

- Glatiramer acetate (mechanism of action in MS is unknown)
immunomodulator
- Natalizumab (mechanism of action in MS is unknown)monoclonal
antibody that binds 4-subunit of integrins on WBCs disrupts interaction
with VCAM-1 (vascular cell adhesion molecule-1) and MAdCAM-1
(mucosal addressin cell adhesion molecule-1) prevents WBCs from
exiting blood vessels to enter subjacent inflamed tissues

Acute disseminated encephalomyelitis

An acute inflammatory and demyelinating disease, ADEM is characterized by

multiple foci of demyelination throughout the brain and spinal cord.
o Usually follows a viral illness, such as measles, mumps, rubella, varicella
zoster, Epstein Barr, herpes simplex or coxsackievirus (also known as
postinfectious encephalitis)
o

Rarely, ADEM may occur after vaccination or bacterial infection. (Though it

can occur at any age, most cases are in children and adolescents.)

Delayed hypersensitivity reaction. Symptoms include fever, headache, seizures and

coma. These symptoms begin 1-3 weeks after infection or vaccination and may
worsen rapidly. Full recovery is seen in most cases, but several patients may recover
with minor residual disability. Average time to recovery is 1-6 months.

Widespread demyelination, particularly in subcortical and central white matter.

Treatment involves high dose intravenous corticosteroids and immunoglobulin.

Guillain-Barre syndrome

Acute inflammatory demyelinating disease which primarily involves peripheral

nerves
Highest incidence in young adults

Autoimmune etiology

Associated with infections. Commonly present with muscle weakness preceded by

herpes virus or Campylobacter jejuni pathogen

Clinical manifestation

Ascending muscle weakness and paralysis

Begins in the lower part of extremities and ascends upwards

Autonomic dysfunction, hypertension, orthostatic hypotension, EKG

changes

Most patients survive but severe cases can have respiratory failure with
death

Hallmark
o

Albumino-cytologic dissociation of CSF

Increased CSF protein concentration with only modest increase in cell count.

Treatment
o

Respiratory support, may require intubation

Plasmapheresis

Intravenous immune globulins

Alzheimer's disease

Clinical findings
o Slow, progressive intellectual deterioration
o

Early stages with loss of recent memory

Late stages with loss of long term memory

Motor difficulty with contractures

Pathology: Alzheimer's is characterized by

1) neuritic (senile) plaques and neurofibrillary tangles, first in the entorhinal
cortex and later in the hippocampus and cerebral cortex.
2) granulovacuolar degeneration in CA 1 region (Sommer's sector) of the
hippocampus

Etiology
o

Unknown etiology but may be related to factors:

Abnormal amyloid gene expression of amyloid beta peptide. May involve

amyloid beta precursor protein (APP) gene on chromosome 21

Down syndrome (trisomy 21) patients develop Alzheimer-like dementia

features

Inheritance of E4 allele of apoprotein E found in chromosome 19 increases

incidence of late-onset Alzheimer dementia

Choline acetyltransferase deficiency, especially in cerebral cortex and

hippocampus

Marked reduction in neurons within nucleus basalis of Meynert

Morphologic & histologic abnormalities

o

Neurofibrillary tangles: intracytoplasmic bundles of filaments with

abnormally phosphorylated tau protein (a microtubule associated protein).
These can be found in the cytoplasm of neurons

Neuritic (senile) plaques: swollen eosinophilic nerve cell processes with

central amyloid core. Found extracellularly

Granulovacuolar degeneration: atrophy of hippocampus

Hirano bodies: intracytoplasmic proximal dendritic eosinophilic inclusions

of actin

Amyloid angiopathy: amyloid deposition around vessels

Generalized cerebral atrophy, widened sulci, narrowed gyri

Neurofibrillary tangles

Other causes of Dementia

Vascular dementia: second most common type of dementia, caused by cerebral

atherosclerosis and vascular insult.
o Three major mechanisms of vascular insult: multiple cortical infarcts, single
and strategic infarct, and small vessel disease.

Binswanger's disease is a form of dementia caused by diffuse subcortical

infarcts, usually resulting from chronic hypertension.

Multi-infarct dementia is the result of severe infarcts, causing a step-wise

decline in function. Emphasis in treatment is on prevention of additional
infarcts.

Infectious diseases: common in immunocompromised patients and the elderly.

o

Chronic infections, such as meningitis caused by Cryptococcus,

neurosyphilis, and Lyme disease, can cause dementia.

HIV-associated neurocognitive disorder (HAND) can cause dementia, and

improves with antiretroviral therapy. HIV associated disorders, such as
progressive multifocal leukoencephalopathy, can also cause dementia.

Prion diseases such a Creutzfeldt-Jakob can present with dementia, which is

rapidly progressive and culminates in death.

Alcoholism is a major cause of dementia. The etiology of this dementia is likely

multifactorial, but thiamine (B-1) deficiency, or Wernicke dementia, is the classic
diagnosis.
o

Wernicke dementia (sometimes called Wernicke-Korsakoff syndrome or

encehpalopathy) is characterized by a triad of ophthalmoplegia, confusion
with confabulation, and ataxia. There is severe atrophy of the brain, most
severely in the mammillary bodies.

Wernicke syndrome may progress rapidly to death. Administration of

thiamine is the appropriate treatment.

Nutritional deficiencies: deficiencies in thiamine (B-1), niacin (B-3), or cobalamin

(B-12) can cause dementia. Administration of the deficient nutrient is typically
curative.

Heavy metal toxicity can cause cognitive impairment, often with peripheral
neuropathy. Wilson's disease is an important genetic disorder resulting in heavy
metal toxicity with neurological impairment. The treatment for heavy metal toxicity
is chelation therapy.

Traumatic brain injury can cause dementia. Dementia pugilistica is a form of

delayed, head-trauma related dementia, seen mainly in boxers.
o

What form of dementia is seen mainly in boxers? What is its etiology?

Frontotemporal lobar degeneration (Pick's disease) is a form of dementia in which

there is atrophy of the frontal and temporal lobes. Frontal lobe degeneration results
in personality changes, abulia, and disinhibition. Temporal lobe degeneration results
in impaired understanding of language and visual information. Pick bodies,
consisting of tau-containing neuronal inclusions, are found.

Dementia with Lewy bodies is a form of dementia that presents with fluctuating
dementia, parkinsonism, and visual hallucinations. It is associated with Alzheimer's
disease, and often patients have pathological changes of both diseases.
o

Lewy bodies are found in the cerebral cortex and the substantia nigra.

Huntington disease

Etiology
o Autosomal dominant
o

Increased CAG trinucleotide repeats within the "Huntingtin" gene on

chromosome 4

Transcription of BDNF gene (neuronal pro-survival factor) is decreased

Especially depletes cholinergic and GABA-ergic neurons

Atrophy of striatum (caudate nucleus and putamen). Loss of the caudate

nucleus, which borders the lateral ventricles, can lead to hydrocephalus ex
vacuo.

Atrophy of frontal cortex with neuronal depletion

Clinical manifestations
o

Delay in clinical manifestations until age 30-40

Course extends 15-20 years with eventual dementia and death

Athetoid movements (hallmark of basal ganglia insult): slow writhing hand

movements

Hypertonicity, fecal/urine incontinence, chorea, dementia and anorexia

Parkinson disease

Etiology
o Loss of the neurons in the substantia nigra (revealed grossly in the
depigmentation of the SN in brain stem section) dopaminergic ouput
from the SNPC to the basal ganglia.
Dopamine acts on 2 receptors in the basal ganglia circuit:
D1: excitatoryactivation of this receptor in movement
D2: inhibitoryactivation of this receptor causes disinhibition of the
thalamus motion
It follows that loss of DA to the basal ganglia causes output to the motor
system bradykinesia.

Depigmentation of substantia nigra and locus ceruleus due to dopamine

depletion.

Lewy bodies: eosinophilic intracytoplasmic inclusions composed of alpha

synuclein in damaged cells are found

Clinical manifestations
o

Usually after age 50

Resting pill-rolling tremor

Masked expressionless facies

Slow movements with muscle rigidity

Shuffling of gait

Other Parkinson like diseases:

o

Postencephalitic parkinsonism: viral etiology, influenza pandemic

Trauma: especially in boxers with brain injury

Drugs and toxins, especially dopamine antagonists, MPTP (1-methyl-4phenyl-1,2,3,6-tetrahydropyridine, an illegal street drug)

Treatment
o

Bromocriptine: ergot alkaloid and partial dopamine agonist

Amantadine: release of dopamine, NMDA receptor inhibition

[1]

L-dopa/Carbidopa: converted to dopamine in the CNS. Unlike dopamine, Ldopa can cross blood brain barrier. Carbidopa is a peripheral decarboxylase
inhibitor that increases the bioavailability of L-dopa to the brain
Selegiline: selective MAO type B inhibitor that prevents dopamine
breakdown
Benztropine: antimuscarinic that improves tremor and rigidity

Amyotrophic lateral sclerosis

Etiology
o Degeneration of upper AND lower motor neurons
o

Sensory neurons are not damaged

Atrophy of lateral corticospinal tracts

Atrophy of anterior motor neurons of spinal cord.

Results in denervation atrophy of muscles

Two forms of ALS:

- Sporadic ALS (most common)
- Familial ALS (5-10% of cases): occurs more than once in a family.
Hereditary defects in superoxide dismutase 1 (autosomal dominant) are
associated with 20% of familial ALS cases.
[1]

Clinical manifestations
o Symmetric atrophy, fasciculation of muscles (lower motor neuron signs)
o

Symmetric hyperreflexia, spasticity and pathological reflexes (upper motor

neuron signs)

Results in rapid course, ending in respiratory failure.

Treatment options:
- Mostly supportive care (pain control, intubation by tracheostomy)
- Riluzole (which blocks glutamatergic neurotransmission by inhibiting glutamate
release and inactivating voltage-gated Na channels) is an FDA-approved medication
that extends survival and/or time to tracheostomy.

Brain Tumors

The most common brain tumors are metastatic (from a primary outside of the brain)
Glioblastoma Multiforme (grade 4 astrocytoma):
o

Most common primary intracranial CNS neoplasm in adults; very poor

prognosis (highly aggressive, rapidly-growing)

Located within white matter of cerebral hemispheres (often in the centrum

semiovale)can spread to the contralateral hemisphere via the corpus
callosum, straddling the cerebral hemispheres to form the classic "butterfly
glioma"

Histopathology:
1. Marked anaplasia (nuclear atypia, pleomorphism) with florid vascular
endothelial hyperplasia secondary to VEGF
2. Pseudopalisading necrosisareas of necrosis and hemorrhage
surrounded by rows of malignant cells

CT with contrast or MRI with contrast: butterfly-shaped space-occupying

lesion with central necrosis outlined by serpiginous, hetergenous contrast
enhancement

Meningioma:
o

Most common benign intracranial neoplasm; second most common primary

intracranial neoplasm in adults

Meningiomas are benign slow-growing tumors that arise from

meningothelial cells (most commonly the arachnoid mater) and are
commonly located parasagitally (near the falx cerebri) or near the
convexities of cerebral hemispheres.

Although asymptomatic for years, meningiomas eventually become large

enough to compress subjacent brain parenchyma patients usually present
with seizures

Histology: whorled pattern of spindle cells with psammoma bodies

(laminated calcifications)

Medulloblastoma:
o

Can occur at any age, but 75% are found in children (median age 9)

Most common intracranial tumor in children

Cerebellum location, can compress fourth ventricle causing hydrocephalus

(Most frequently arises in the posterior fossa)

Histology: sheets of closely packed cells with rosette or perivascular

pseudorosette pattern

Highly malignant, considered a primitive neuroectodermal tumor

Despite being incredibly malignant, medulloblastomas are also

radiosensitive

Neuroblastoma: [1]
o

Occurs almost exclusively in children

Primary CNS neuroblastomas are very rare and usually cerebral.

Neuroblastomas are most often found in adrenal medulla but can be found
anywhere along the sympathetic chain

Most common extracranial solid cancer in infancy

Associated with N-myc oncogene amplification. Amplification poor

prognosis.

Systemic metastases, especially to bone, have been observed

Retinoblastoma:

Most common primary ocular malignancy of childhood (generally found in

children under age 6)

Retina location, unilateral or bilateral

Commonly discovered on fundoscopic exam, which reveals leukocoria:

instead of seeing a red reflex, the examiner will see a white mass.

Linked to homozygous deletion or inactivation of Rb gene (chromosome

13)

Schwannoma:
o

Acoustic schwannoma: third most common primary intracranial neoplasm.

Usually unilateral.

Typically presents in middle-aged patients with progressive sensorineural

hearing loss, tinnitus

Occur on the vestibular division of CN VIII at the cerebellopontine angle

Encapsulated tumor arising from Schwann cells

Histology: Nuclei arranged in "palisades"

Benign and resectable

Bilateral acoustic neuromas (benign schwannomas usually occurring on the

vestibular division of CN VIII) are diagnostic of neurofibromatosis type 2

Oligodendroglioma:
o

Typically affects middle-aged pts

Cerebral location

Histology: closely packed cells with large nuclei surrounded by clear

halo of cytoplasm"fried egg" appearance

Slow growing and rare

Astrocytoma:
o

Affects young children

Posterior fossa location and circumscribed

Histology: Rosenthal fiberseosinophilic corkscrew fibers

Benign, low grade, good prognosis

Glioblastoma pseudopalisade arrangement

Meningioma whorled pattern

Schwannoma

Oligodendroglioma- fried egg appearance

Astrocytoma rosenthal fibers

Seizures

Seizures may be partial (affects one area of the brain) or generalized (diffuse)
However, partial seizures may progress to be generalized

Epilepsy: used to describe condition of recurrent seizures

Causes for epilepsy: genetic, infection, trauma, stroke, metabolic (hypo or

hypernatremia)

Simple partial seizures

Patient remains conscious

Can manifest as motor, sensory, psychic, or autonomic changes

Treatment: all anti-seizure drugs work effectively

Complex partial seizures

o

Patient has impaired consciousness

Treatment: all anti-seizure drugs work effectively

Absence (Petit Mal) seizures

o

Usually in children, manifest as a blank stare

Treatment: First line anti-seizures drug treatment is ethosuximide. Valproic

acid is used as a second line agent

Myoclonic seizures
o

Repetitive jerks of the body or extremities

Treatment: First line agent is valproic acid.

Tonic-Clonic (Grand Mal) seizures

Patient is tonic (stiff) and then becomes clonic (jerking movements)

The 3 first line anti-epileptics for tonic-clonic seizures have a similar

mechanism ( Na channel inactivation) and can be remembered by "PVC":
1. Phenytoin (also first line for prophylaxis of status epilepticus)
2. Valproic acid (also used for myoclonic seizures)
3. Carbamazepine (also first line for trigeminal neuralgia)

Status epilepticus
o

Life threatening, persistent seizure activity in the brain

Treatment: First line anti-seizure drugs are benzodiazepines, such as

diazepam. First line drug for prophylaxis is phenytoin to increase seizure
threshold

Anti-seizure drugs

Phenytoin
o Increases Na channel inactivation
o

Inhibits release of glutamate, which is an excitatory neurotransmitter

Is a Class IB antiarrhythmic

Induces cytochrome P450

Side effects:
- Neuro S/Sx: diplopia, nystagmus, ataxia
- Gingival hyperplasia
- Hirsutism
- SLE-like syndrome (ie, drug-induced lupus)
- folate absorption folate deficiency megaloblastic anemia
- vitamin D absorption vitamin D deficiency osteomalacia
[1]

Carbamazepine
o Increases Na channel inactivation
o

First line agent for tonic-clonic seizures (as is phenytoin) ; first line agent for
trigeminal neuralgia

Induces cytochrome P450

Side effects/toxicities:
- Hematologic S/Sx: agranulocytosis, aplastic anemia

- Stevens-Johnson syndrome
- SIADH dilutional hyponatremia
- vitamin D absorption vitamin D deficiency osteomalacia
- Teratogenic effects: spina bifida, cleft lip/palate
[2] [3] [4]

Gabapentin
o Increases GABA (inhibitory neurotransmitter) release indirectly by acting on
N-type Ca channels.
o

Can be used to treat peripheral neuropathy pain syndromes

Side effects: sedation, ataxia, mild weight gain

Ethosuximide
o

Mechanism is controversial, blockage of T type calcium channels in

thalamic neurons

First line agent for absence seizures

Side effects:
- Stevens-Johnson syndrome
- urticaria
- GI symptoms, fatigue, headache

Lamotrigine
o

Blocks voltage gated Na channels

Side effect: Stevens-Johnson syndrome

Topiramate
o

Inhibits excitatory neurotransmission through action on AMPA and kainate

receptors

Enhances GABA-activated chloride channels and is a sodium channel

blocker

Side effects: kidney stones (due to a weak inhibition of carbonic anhydrase),

somnolence and loss of appetite

Valproic Acid
o

Blocks voltage gated Na channels

Direct GABA agonist

First line agent for tonic clonic seizures

Side effects: GI symptoms, hepatotoxicity, spina bifida in fetus

(contraindicated in pregnancy), weight gain, thrombocytopenia

Benzodiazepines and Barbiturates

Benzodiazepines (e.g., diazepam, lorazepam, midazolam, chlordiazepoxide)

o Potentiates the effect of GABA by increasing the frequency of chloride
channel opening
o

First line agents to treat alcohol withdrawalknown as Delirium Tremens

(DTs) if the withdrawal is severe

First line agents for status epilepticus

Toxicity: sedation, respiratory depression, tolerance/dependence

Treatment of toxicity: flumazenil, a competitive antagonist at GABA

receptor. Flumazenil has a short half-life and has no effect in the absence of
benzodiazepines.

Barbiturates (e.g., phenobarbital, thiopental, secobarbital)

o

Potentiates the effect of GABA by increasing the duration of chloride

channel opening

Treats anxiety and seizures

Unlike benzodiazepines, barbiturates induce the cytochrome P450 system

barbiturates are contraindicated in porphyrias:
Barbiturates synthesis of cytochrome P450 enzymes heme
(because P450 enzymes contain heme heme is required to synthesize P450
enzymes) shortage of heme substrate stimulates -aminolevulinic acid
synthase activity -aminolevulinic acid levels of downstream
intermediates in the heme synthesis pathway, thereby exacerbating
porphyrias (eg, acute intermittent porphyria, porphyria cutanea tarda)

In addition to inducing the cytochrome P450 system, barbiturates also

increase the metabolism of several drugs, which often decreases the
pharmacological effect of these drugs

Toxicity: sedation, respiratory depression, cardiovascular depression

Treatment of toxicity: only supportive measures, there is no antagonist

Opioid analgesics

Opioids act as agonist on mu (morphine), delta (enkephalin) and kappa (dynorphin)

receptors

Clinical usage:
o

Pain, mu agonist at substantia gelatinosa of spinal dorsal horn decreases

substance P

Dextromethorphan is used for cough suppression; meperidine has

anticholinergic properties and metabolites with pro CNS-seizure activity

Methadone is used as maintenance for addicts

Acute pulmonary edema

Toxicity
o

Respiratory depression

Additive CNS depression when used with other drugs

Addiction

Constipation (tolerance does not develop to constipation)

Miosis (tolerance does not develop to miosis)

Treatment of toxicity
o

Naloxone is a receptor competitive antagonist given intravenously for the

emergent treatment of respiratory depression due to opioid overdose.
Overusage may cause acute pulmonary edema.

Naltrexone is an opioid receptor antagonist used in the long-term treatment

of addicts to decrease craving for alcohol and opioids.

Sumatriptan

5HT serotonin agonist that causes vasoconstriction

o Used to treat: acute migraines and cluster headaches
o

Toxicity: coronary vasospasm (contraindicated in patients with Prinzmetals

angina)

Dantrolene

Muscle relaxant - prevents the calcium release from sarcoplasmic reticulum in

skeletal muscle
o Remember, actin = thin filaments, myosin = thick filaments
o

Troponin = protein complex consisting of T (tropomyosin binding), I

(inhibitory), and C (calcium binding) subunits. In resting muscle troponin I
binds to actin.

Tropomyosin = inhibitory protein that overlays the myosin binding sites on

actin in resting muscle

Calcium binds to troponin C, and this causes troponin I to release its hold on
actin. Tropomyosin can then move away from the binding groove, and
myosin heads can bind to actin filament.

Dantrolene decreases the amount of available Ca and thus inhibits the

excitation-contraction coupling.

May act on the ryanodine receptor, has high lipid solubility

Used to treat:
o

1) Malignant Hyperthermia: a genetically predisposed hypermetabolic

syndrome caused by exposure to inhalation anesthetics or succinylcholine

2) Neuroleptic Malignant Syndrome: a toxic hypermetabolic side effect in

patients using combination antipsychotic drugs or associated with
withdrawal of L-Dopa medication. Such side effects include rigidity,
autonomic instability, fever, and coma. Unlike malignant hyperthermia,
there is no genetic predisposition.

Anesthetic Agents & ICP

Intracranial cavity is fixed; therefore, intracranial pressure (ICP) is dependent on

cerebral blood volume
Except for ketamine, all intravenous induction agents (propofol, barbiturates,
benzodiazepines) and opioids decrease cerebral metabolic rate and cerebral blood
volume [1] [2]
o

Ketamine increases cerebral metabolic rate and cerebral blood volume.

Thus, it is contraindicated in situations of increased ICP.

Note: other vasodilators such as nitroglycerin and calcium channel blockers will
increase ICP by increased cerebral blood volume from vasodilatation of cerebral
blood vessels. Beware of using these agents in situations of increased ICP such as
head bleed