Autonomic nervous system

The autonomic nervous system

Blue = parasympathetic
Red = sympathetic

The autonomic nervous system (ANS or visceral nervous system) is the part of theperipheral nervous
system that acts as a control system functioning largely below the level of consciousness, and
controls visceral functions. The ANS affects heart rate, digestion,respiration rate, salivation, perspiration,
diameter of the pupils, micturition (urination), andsexual arousal. Whereas most of its actions are involuntary,
some, such as breathing, work in tandem with the conscious mind.
It is classically divided into two subsystems: the parasympathetic nervous system andsympathetic nervous
system. Relatively recently, a third subsystem of neurons that have been named 'non-adrenergic and non-
cholinergic' neurons (because they use nitric oxide as a neurotransmitter) have been described and found to be
integral in autonomic function, particularly in the gut and the lungs.
With regard to function, the ANS is usually divided into sensory (afferent) and motor (efferent) subsystems.
Within these systems, however, there are inhibitory and excitatory synapsesbetween neurons.
The enteric nervous system is sometimes considered part of the autonomic nervous system, and sometimes
considered an independent system.
Anatomy
ANS innervation is divided into sympathetic nervous system and parasympathetic nervous system divisions.
The sympathetic division has thoracolumbar “outflow”, meaning that the neurons begin at the thoracic and
lumbar (T1-L2) portions of the spinal cord. The parasympathetic division has craniosacral “outflow”, meaning
that the neurons begin at the cranial nerves (CN 3, CN7, CN 9, CN10) and sacral (S2-S4) spinal cord.
The ANS is unique in that it requires a sequential two-neuron efferent pathway; the preganglionic neuron must
first synapse onto a postganglionic neuron before innervating the target organ. The preganglionic, or first,
neuron will begin at the “outflow” and will synapse at the postganglionic, or second, neuron’s cell body. The
post ganglionic neuron will then synapse at the target organ.
Sympathetic division
The sympathetic division (thoracolumbar outflow) consists of cell bodies in the lateral horn of spinal
cord (intermediolateral cell columns) of the spinal cord from T1 to L2. These cell bodies are GVE neurons
(general visceral efferent), and are the preganglionic neurons. There are several locations upon which
preganglionic neurons can synapse for their postganglionic neurons:
 Paravertebral ganglia of the sympathetic chain (these run on either side of the vertebral bodies)
 Prevertebral ganglia (celiac ganglia, superior mesenteric ganglia, inferior mesenteric ganglia)
 Chromaffin cells of adrenal medulla (this is the one exception to the two-neuron pathway rule: synapse
is direct onto cell bodies)
These ganglia provide the postganglionic neurons from which innervation of target organs follows. Examples of
splanchnic (visceral) nerves are:
 Cervical cardiac nerves & thoracic visceral nerves which synapse in the sympathetic chain
 Thoracic splanchnic nerves (greater, lesser, least) which synapse in the prevertebral ganglion
 Lumbar splanchnic nerves which synapse in the prevertebral ganglion
 Sacral splanchnic nerves which synapse in the inferior hypogastric plexus
These all contain afferent (sensory) nerves as well, also known as GVA neurons (general visceral afferent).
Parasympathetic division
The parasympathetic division (craniosacral outflow) consists of cell bodies from one of two
locations: brainstem (Cranial Nerves 3, 7, 9, 10) or sacral spinal cord (S2, S3, S4). These are the preganglionic
neurons, which synapse with postganglionic neurons in these locations:
 Parasympathetic ganglia of the head (Ciliary (CN3), Submandibular (CN7), Pterygopalatine (CN7),
Otic (CN9))
 In or near wall of organ innervated (hfVagus (CN10), Sacral nerves (S2, S3, S4))
These ganglia provide the postganglionic neurons from which innervations of target organs follows. Examples
are:
 The preganglionic parasympathetic splanchnic (visceral) nerves
 Vagus nerve, which wanders through the thorax and abdominal regions innervating, among other
organs, the heart, lungs, liver and stomach
Sensory neurons
The sensory arm is made of “primary visceral sensory neurons” found in the peripheral nervous system (PNS),
in “cranial sensory ganglia”: the geniculate, petrosal and nodose ganglia, appended respectively to cranial
nerves VII, IX and X. These sensory neurons monitor the levels of carbon dioxide, oxygen and sugar in the
blood, arterial pressure and the chemical composition of the stomach and gut content. (They also convey the
sense of taste, a conscious perception). Blood oxygen and carbon dioxide are in fact directly sensed by the
carotid body, a small collection of chemosensors at the bifurcation of the carotid artery, innervated by the
petrosal (IXth) ganglion. Primary sensory neurons project (synapse) onto “second order” or relay visceral
sensory neurons located in the medulla oblongata, forming the nucleus of the solitary tract (nTS), that
integrates all visceral information. The nTS also receives input from a nearby chemosensory center, the area
postrema, that detects toxins in the blood and the cerebrospinal fluid and is essential for chemically induced
vomiting or conditional taste aversion (the memory that ensures that an animal which has been poisoned by a
food never touches it again). All these visceral sensory informations constantly and unconsciously modulate
the activity of the motor neurons of the ANS
Motor neurons
Motor neurons of the ANS are also located in ganglia of the PNS, called “autonomic ganglia”. They belong to
three categories with different effects on their target organs (see below “Function”): sympathetic,
parasympathetic and enteric.
Sympathetic ganglia are located in two sympathetic chains close to the spinal cord: the prevertebral and pre-
aortic chains. Parasympathetic ganglia, in contrast, are located in close proximity to the target organ:
the submandibular ganglion close to salivary glands, paracardiac ganglia close to the heart etc... Enteric
ganglia, which as their name implies innervate the digestive tube, are located inside its walls and collectively
contain as many neurons as the entire spinal cord, including local sensory neurons, motor neurons and
interneurons. It is the only truly autonomous part of the ANS and the digestive tube can function surprisingly
well even in isolation. For that reason the enteric nervous system has been called “the second brain”.
The activity of autonomic ganglionic neurons is modulated by “preganglionic neurons” (also called improperly
but classically "visceral motoneurons") located in the central nervous system. Preganglionic sympathetic
neurons are in the spinal cord, at thoraco-lumbar levels. Preganglionic parasympathetic neurons are in the
medulla oblongata (forming visceral motor nuclei: the dorsal motor nucleus of the vagus nerve (dmnX),
the nucleus ambiguus, and salivatory nuclei) and in the sacral spinal cord. Enteric neurons are also modulated
by input from the CNS, from preganglionic neurons located, like parasympathetic ones, in the medulla
oblongata (in the dmnX).
The feedback from the sensory to the motor arm of visceral reflex pathways is provided by direct or indirect
connections between the nucleus of the solitary tract and visceral motoneurons.
Function
Sympathetic and parasympathetic divisions typically function in opposition to each other. But this opposition is
better termed complementary in nature rather than antagonistic. For an analogy, one may think of the
sympathetic division as the accelerator and the parasympathetic division as the brake. The sympathetic
division typically functions in actions requiring quick responses. The parasympathetic division functions with
actions that do not require immediate reaction. Consider sympathetic as "fight or flight" and parasympathetic as
"rest and digest".
However, many instances of sympathetic and parasympathetic activity cannot be ascribed to "fight" or "rest"
situations. For example, standing up from a reclining or sitting position would entail an unsustainable drop in
blood pressure if not for a compensatory increase in the arterial sympathetic tonus. Another example is the
constant, second to second modulation of heart rate by sympathetic and parasympathetic influences, as a
function of the respiratory cycles. More generally, these two systems should be seen as permanently
modulating vital functions, in usually antagonistic fashion, to achieve homeostasis. Some typical actions of the
sympathetic and parasympathetic systems are listed below.
Sympathetic nervous system
Promotes a "fight or flight" response, corresponds with arousal and energy generation, and inhibits digestion.
 Diverts blood flow away from the gastro-intestinal (GI) tract and skin via vasoconstriction.
 Blood flow to skeletal muscles and the lungs is enhanced (by as much as 1200% in the case of
skeletal muscles).
 Dilates bronchioles of the lung, which allows for greater alveolar oxygen exchange.
 Increases heart rate and the contractility of cardiac cells (myocytes), thereby providing a mechanism
for the enhanced blood flow to skeletal muscles.
 Dilates pupils and relaxes the ciliary muscle to the lens, allowing more light to enter the eye and far
vision.
 Provides vasodilation for the coronary vessels of the heart.
 Constricts all the intestinal sphincters and the urinary sphincter.
 Inhibits peristalsis.
 Stimulates orgasm.
 Diabetes peristalsis
Parasympathetic nervous system
Promotes a "rest and digest" response, promotes calming of the nerves return to regular function, and
enhances digestion.
 Dilates blood vessels leading to the GI tract, increasing blood flow. This is important following the
consumption of food, due to the greater metabolic demands placed on the body by the gut.
 The parasympathetic nervous system can also constrict the bronchiolar diameter when the need for
oxygen has diminished.
 Dedicated cardiac branches of the Vagus and thoracic Spinal Accessory nerves
impart Parasympathetic control of the Heart orMyocardium.
 During accommodation, the parasympathetic nervous system causes constriction of the pupil and
contraction of the ciliary muscle to the lens, allowing for closer vision.
 The parasympathetic nervous system stimulates salivary gland secretion, and accelerates peristalsis,
so, in keeping with the rest and digest functions, appropriate PNS activity mediates digestion of food and
indirectly, the absorption of nutrients.
 Is also involved in erection of genitals, via the pelvic splanchnic nerves 2–4.
 Stimulates sexual arousal.
Neurotransmitters and pharmacology
At the effector organs, sympathetic ganglionic neurons release noradrenaline (norepinephrine), along with
other cotransmitters such as ATP, to act on adrenergic receptors, with the exception of the sweat glands and
the adrenal medulla:
 Acetylcholine is the preganglionic neurotransmitter for both divisions of the ANS, as well as the
postganglionic neurotransmitter of parasympathetic neurons. Nerves that release acetylcholine are said to
be cholinergic. In the parasympathetic system, ganglionic neurons use acetylcholine as a neurotransmitter,
to stimulate muscarinic receptors.
 At the adrenal cortex, there is no postsynaptic neuron. Instead the presynaptic neuron releases
acetylcholine to act on nicotinic receptors.
 Stimulation of the adrenal medulla releases adrenaline (epinephrine) into the bloodstream which will
act on adrenoceptors, producing a widespread increase in sympathetic activity.
The following table reviews the actions of these neurotransmitters as a function of their receptors.
Nervous system
Target Sympathetic (adrenergic) Parasympathetic (muscarinic)
α1: contracts M3: relaxes
Pupil dilator muscle
(causes mydriasis) (causes miosis)
β2: relaxes M3: contracts
Ciliary muscle
(causes long-range focus) (causes short-range focus)
Digestive system
Target Sympathetic (adrenergic) Parasympathetic (muscarinic)
β: stimulates
M3: stimulates watery
salivary glands: secretions viscous, amylase secretions
secretions
α1: stimulates potassium cation
lacrimal glands (tears) β: stimulates protein secretion ---
kidney (renin) β1: secretes ---
parietal cells --- M1: Gastric acid secretion
α1,
liver ---
β2: glycogenolysis, gluconeogenesis
adipose cells β1, β3: stimulates lipolysis ---
GI tract (smooth muscle)
α1, α2, β2: decreases M3, (M1) : increases
motility
sphincters of GI tract α1 , α2 , β2: contracts M3: relaxes
glands of GI tract no effect M3: secretes
Endocrine system
Target Sympathetic (adrenergic) Parasympathetic (muscarinic)
pancreas(islets α2: decreases secretion from beta cells, M3 increases stimulation from alpha
) increases secretion fromalpha cells cells andbeta cells
adrenal N (nicotinic ACh receptor):
---
medulla secretes epinephrine and norepinephrine
Urinary system
Target Sympathetic (adrenergic) Parasympathetic (muscarinic)
Detrusor urinae muscle of bladder wall β2: relaxes M3: contracts
urethral sphincter (internal) α1: contracts relaxes
sphincter α1: contracts; β2 relaxes M3: relaxes
Reproductive system
Target Sympathetic (adrenergic) Parasympathetic (muscarinic)
α1: contracts (pregnant)
uterus ---
β2: relaxes (non-pregnant)
genitalia α1: contracts (ejaculation) M3: erection
Integumentary system
Parasympathetic (muscarinic
Target Sympathetic (muscarinic and adrenergic)
)
sweat M: stimulates (major contribution); α1: stimulates
---
gland secretions (minor contribution)
arrector pili α1: stimulates ---
Sympathetic nervous system
Brain: Sympathetic nervous system

The sympathetic nervous system extends from the thoracic to

lumbar vertebrae and has connections with the thoracic,cat, and
pelvic plexuses.
Latin Pars sympathica divisionis autonomici systematis nervosi
The (ortho-) sympathetic nervous system (SNS) is one of the three parts of the autonomic nervous system,
along with the enteric and parasympathetic systems. Its general action is to mobilize the body's resources
under stress; to induce the fight-or-flight response. It is, however, constantly active at a basal level in order to
maintain homeostasis.
Overview
Along side the other two components of the autonomic nervous system, the sympathetic nervous system aids
in the control of most of the body's internal organs. Stress - as in theflight-or-fight response - and so may be
thought to counteract the parasympathetic system, which generally works to promote maintenance of the body
at rest. In truth, the functions of both systems are not so straightforward, but this is a useful rule of thumb.
There are two kinds of neurons involved in the transmission of any signal through the sympathetic system; pre-
and post- ganglionic. The shorter preganglionic neurons originate from the thoracolumbar region of the spinal
cord (levels T1 - L2, specifically) and travel to a ganglion, often one of the paravertebral ganglia, where they
synapse with a postganglionic neuron. From there, the long postganglionic neurons extend across most of the
body.
At the synapses within the ganglia, preganglionic neurons release acetylcholine, aneurotransmitter which
activates nicotinic acetylcholine receptors on postganglionic neurons. In response to this stimulus
postganglionic neurons - with two important exceptions - release norepinephrine, which activates adrenergic
receptors on the peripheral target tissues. It is the activation of target tissue receptors which causes the effects
associated with the sympathetic system.
The two exceptions mentioned above are postganglionic neurons innervating sweat glands - which release
acetylcholine for the activation ofmuscarinic receptors - and the adrenal medulla. The adrenal
medulla develops in tandem with the sympathetic nervous system, and acts as a modified sympathetic
ganglion: synapses occur between pre- and post- ganglionic neurons within it, but the post ganglionic neurons
do not leave the medulla; instead they directly release norepinephrine and epinephrine into the blood.
Function
Organ Effect
Eye Dilates pupil
Heart Increases rate and force of contraction
Lungs Dilates bronchioles
Digestive tract Inhibits peristalsis
Kidney Increases renin secretion
Penis Promotes ejaculation
Examples of sympathetic system action on various organs.
The sympathetic nervous system is responsible for up- and down-regulating many homeostatic mechanisms in
living organisms. Fibers from the SNS innervate tissues in almost every organ system, providing at least some
regulatory function to things as diverse as pupil diameter,gut motility, and urinary output. It is perhaps best
known for mediating the neuronal and hormonal stress response commonly known as thefight-or-flight
response. This response is also known as sympatho-adrenal response of the body, as
the preganglionic sympathetic fibers that end in the adrenal medulla (but also all other sympathetic fibers)
secrete acetylcholine, which activates the great secretion of adrenaline (epinephrine) and to a lesser extent
noradrenaline (norepinephrine) from it. Therefore, this response that acts primarily on the cardiovascular
system is mediated directly via impulses transmitted through the sympathetic nervous system and indirectly
via catecholamines secreted from the adrenal medulla.
Some evolutionary theorists suggest that the sympathetic nervous system operated in early organisms to
maintain survival as the sympathetic nervous system is responsible for priming the body for action. One
example of this priming is in the moments before waking, in which sympathetic outflow spontaneously
increases in preparation for action.
Organization
Sympathetic nerves originate inside the vertebral column, toward the middle of the spinal cord in
the intermediolateral cell column (or lateral horn), beginning at the first thoracic segment of the spinal cord and
are thought to extend to the second or third lumbar segments. Because its cells begin in the thoracic and
lumbar regions of the spinal cord, the SNS is said to have a thoracolumbar outflow. Axons of these nerves
leave the spinal cord through the anterior rootlet/root. They pass near the spinal (sensory) ganglion, where they
enter the anterior rami of the spinal nerves. However, unlike somatic innervation, they quickly separate out
through white rami connectors (so called from the shiny white sheaths of myelin around each axon) which
connect to the either the paravertebral (which lie near the vertebral column) or prevertebral (which lie near the
aortic bifurcation) ganglia extending alongside the spinal column.
In order to reach the target organs and glands, the axons must travel long distances in the body, and, to
accomplish this, many axons relay their message to a second cell through synaptic transmission. The ends of
the axons link across a space, the synapse, to the dendrites of the second cell. The first cell (the presynaptic
cell) sends a neurotransmitter across the synaptic cleft where it activates the second cell (the postsynaptic
cell). The message is then carried to the final destination.
Presynaptic nerves' axons terminate in either the paravertebral ganglia or prevertebral ganglia. This can occur
through one of four methods:
1. The nerve enters the paravertebral ganglion at the level of its originating spinal nerve, and then ascends to a
more superior paravertebral ganglion, where it synapses with the postsynaptic cell.
2. The nerve enters the paravertebral ganglion at the level of its originating spinal nerve and synapses with the
postsynaptic cell at that level.
3. The nerve enters the paravertebral ganglion at the level of its originating spinal nerve, and then descends to
a more inferior paravertebral ganglion, where it synapses with the postsynaptic cell.
4. The nerve enters the paravertebral ganglion at the level of its originating spinal nerve and then descends to
a prevertebral ganglion, where it synapses with the postsynaptic cell.
The postsynaptic cell then goes on to innervate the targeted end effector (ie gland, smooth muscle, etc.).
Because paravertebral and prevertebral ganglia are relatively close to the spinal cord, presynaptic neurons are
generally much shorter than their postsynaptic counterparts, which must extend throughout the body to reach
their destinations.
A notable exception to the routes mentioned above is the sympathetic innervation of the suprarenal (adrenal)
glands. In this case, presynaptic neurons pass through paraverterbral ganglia, on through prevertebral ganglia
and then synapse directly with suprarenal tissue. This tissue consists of cells that have pseudo-neuron like
qualities in that when activated by the presynaptic neuron, they will release their neurotransmitter (epinephrine)
directly into the blood stream.
In the SNS and other components of the peripheral nervous system, these synapses are made at sites called
ganglia. The cell that sends its fiber is called a preganglionic cell, while the cell whose fiber leaves the ganglion
is called a postganglionic cell. As mentioned previously, the preganglionic cells of the SNS are located between
the first thoracic segment and third lumbar segments of the spinal cord. Postganglionic cells have their cell
bodies in the ganglia and send their axons to target organs or glands.
The ganglia include not just the sympathetic trunks but also the cervical ganglia (superior, middle and inferior),
which sends sympathetic nerve fibers to the head and thorax organs, and the celiac and mesenteric
ganglia (which send sympathetic fibers to the gut).
Information transmission
Messages travel through the SNS in a bidirectional flow. Efferent messages can trigger changes in different
parts of the body simultaneously. For example, the sympathetic nervous system can accelerate heart rate;
widen bronchial passages; decrease motility (movement) of thelarge intestine; constrict blood vessels;
increase peristalsis in the esophagus; cause pupillary dilation, piloerection (goose bumps) and perspiration
(sweating); and raise blood pressure. Afferent messages carry sensations such as heat, cold, or pain.
The first synapse (in the sympathetic chain) is mediated by nicotinic receptors physiologically activated by
acetylcholine, and the target synapse is mediated by adrenergic receptors physiologically activated by either
noradrenaline (norepinephrine) or adrenaline (epinephrine). An exception is with sweat glands which receive
sympathetic innervation but have muscarinic acetylcholine receptors which are normally characteristic of
Parasympathetic nervous system. Another exception is with certain deep muscle blood vessels, which dilate
(rather than constrict) with an increase in sympathetic [Link] is because of the presence of more beta2
receptors(rather than alpha1 which are frequently found on other vessels).
Sympathicotonia
Sympathicotonia is a stimulated condition of the sympathetic nervous system, marked by vascular
spasm, elevated blood pressure, and goose bumps.
Parasympathetic nervous system
Brain: Parasympathetic nervous system

Autonomic nervous system innervation, showing the sympathetic

and parasympathetic (craniosacral) systems, in red and blue,
respectively
Latin Pars parasympathica divisionis autonomici systematis
nervosi
The parasympathetic nervous system (PSNS) is one of the three main divisions of theautonomic nervous
system (ANS). The ANS is responsible for regulation of internal organs and glands, which occurs
unconsciously. The parasympathetic system specifically is responsible for stimulation of activities that occur
when the body is at rest, includingsalivation, lacrimation, urination, digestion and defecation. Its action is
described as being complementary to that of one of the other main branches of the ANS, the sympathetic
nervous system, which is responsible for stimulating activities associated with the fight-or-flight response.
Because of this relationship, the action of the parasympathetic nervous system is often described as "rest and
digest".
Relation to sympathetic nervous system
Sympathetic and parasympathetic divisions typically function in opposition to each other. But this opposition is
better understood as complementary in nature rather than antagonistic. For an analogy, one may think of the
sympathetic division as the accelerator and the parasympathetic division as the brake. The sympathetic
division typically functions in actions requiring quick responses. The parasympathetic division functions with
actions that do not require immediate reaction. A useful acronym to summarize the functions of the
parasympathetic nervous system is SLUDD (salivation, lacrimation, urination, digestion and defecation).
Physical location
The parasympathetic nerves (PSN) are autonomic (aka "visceral") branches of the peripheral nervous
system (PNS). Parasympathetic nerve fibers arise from the central nervous system with the S2, S3, and
S4 spinal nerves and from the third, seventh, ninth, and tenth cranial nerves. Because of its location the
parasympathetic system is commonly referred to as having "craniosacral outflow", which stands in contrast to
the sympathetic nervous system which is said to have "thoracolumbar outflow".
The parasympathetic nerves that arise from the S2, S3, and S4 spinal nerves are commonly referred to as
the pelvic splanchnic nerves or the "nervi erigentes".
Pathways
As is true in the sympathetic nervous system, efferent parasympathetic nerve signals are carried from the
central nervous system to their targets by a system of two neurons. The first neuron in this pathway is referred
to as the preganglionic or presynaptic neuron. Its cell body sits in the central nervous system and its axon
usually extends to a ganglion somewhere else in the body where it synapses with thedendrites of the second
neuron in the chain. This second neuron is referred to as the postganglionic or postsynaptic neuron.
The axons of presynaptic parasympathetic neurons are usually long: they extend from the CNS into a ganglion
that is either very close to or embedded in their target organ. As a result, the postsynaptic parasympathetic
nerve fibers are very short.
In the cranium, preganglionic PSN (CN III, CN VII, and CN IX) usually arise from specific nuclei in the Central
Nervous System (CNS) and synapse at one of four parasympathetic ganglia: ciliary, pterygopalatine, otic,
or submandibular. From these four ganglia the PSN complete their journey to target tissues via CN V
(trigeminal) branches (ophthalmic nerve CN V1, maxillary nerve CN V2, mandibular nerve CN V3).
The vagus nerve (CN X) does not participate in these cranial ganglion as most of its PSN fibers are destined
for a broad array of ganglia on or near thoracic vicera (esophagus, trachea, heart, lungs) and abdominal
viscera (stomach, pancreas, liver, kidneys). It travels all the way down to the midgut/hindgut junction, which
occurs just before the splenic flexure of the transverse colon at a point called "cannon bohm".
The pelvic splanchnic efferent preganglionic nerve cell bodies reside in the lateral gray horn of the spinal
cord at the S2-S4 spinal [Link] axons continue away from the CNS to synapse at an autonomic ganglion.
The PSN ganglion where these preganglionic neurons synapse will be close to the organ of innervation. This
differs from the sympathetic nervous system, where synapses between pre- and post-ganglionic efferent
nerves generally occur at ganglia that are farther away from the target organ.
Sensation
The afferent fibers of the autonomic nervous system, which transmit sensory information from the internal
organs of the body back to the central nervous system, are not divided into parasympathetic and sympathetic
fibers as the efferent fibers are. Instead, autonomic sensory information is conducted by general visceral
afferent fibers.
General visceral afferent sensations are mostly unconscious visceral motor reflex sensations from hollow
organs and glands that are transmitted to the CNS. While the unconscious reflex arcs normally are
undetectable, in certain instances they may send pain sensations to the CNS masked as referred pain. If
the peritoneal cavity becomes inflamed or if the bowel is suddenly distended your body will interpret the
afferent pain stimulus as somatic in origin. This pain is usually non-localized. The pain is also usually referred
to dermatomes that are at the same spinal nerve level as the visceral afferent synapse.
Cranial Nerve Parasympathetic Paths and Control
The oculomotor nerve is responsible for several parasympathetic functions related to the eye. The oculomotor
PNS fibers originate in theEdinger-Westphal nucleus in the CNS and travel through the superior orbital
fissure to synapse in the ciliary ganglion located just behind the orbit (eye). From the ciliary ganglion the
postganglionic PSN fibers leave via short ciliary nerve fibers, a continuation of the nasociliary nerve (a branch
of ophthalmic division of the trigeminal nerve, CN V1). The short ciliary nerves innervate the orbit to control the
ciliary muscle (responsible for accommodation) and the sphincter pupillae muscle which is responsible for
miosis or constriction of the pupil (in response to light or accommodation).
The parasympathetic aspect of the facial nerve controls secretion of the sublingual and submandibular salivary
glands, the lacrimal gland, and the glands associated with the nasal cavity. The preganglionic fibers originate
within the CNS in the superior salivatory nucleus and leave as the intermediate nerve (which some consider a
separate cranial nerve altogether) to connect with the facial nerve just distal (further out) to it surfacing the
CNS. Just after the facial nerve geniculate ganglion (general sensory ganglion) in the temporal bone, the facial
nerve gives off two separate parasympathetic nerves. The first is the greater petrosal nerve and the second is
the chorda tympani. The greater petrosal nerve travels through the middle ear and eventually combines with
the deep petrosal nerve (sympathetic fibers) to form the nerve of the pterygoid canal. The PSN fibers of the
nerve of the pterygoid canal synapse at the pterygopalatine ganglion, which is closely associated with the
maxillary division of the trigeminal nerve (CN V2). The postganglionic PSN fibers leave the pterygopalatine
ganglion in several directions. One division leaves on the zygomatic division of CN V2 and travels on a
communicating branch to unite with the lacrimal nerve (branch of the ophthalmic nerve of CN V 1) before
synapsing at the lacrimal gland. These PSN to the lacrimal gland control tear production.
A separate group of PSN leaving from the pterygopalatine ganglion are the descending palatine nerves (CN
V2 branch) which include the greater and lesser palatine nerves. The greater palatine PSN synapse on the hard
palate and regulate mucus glands located there. The lesser palatine nerve synapses at the soft palate and
controls sparse taste receptors and mucus glands. Yet another set of divisions from the pterygopalatine
ganglion are the posterior, superior, and inferior lateral nasal nerves; and the nasopalatine nerves (all branches
of CN V2, maxillary division of the trigeminal nerve) that bring PSN to glands of the nasal mucosa. The second
PSN branch that leaves the facial nerve is the chorda tympani. This nerve carries secretomotor fibers to
the submandibular and sublingual glands. The chorda tympani travels through the middle ear and attaches to
the lingual nerve (mandibular division of trigeminal, CN V3). After joining the lingual nerve the preganglionic
fibers synapse at the submandibular ganglion and send postganglionic fibers to the sublingual and
submandibular salivary glands.
The glossopharyngeal nerve, CNIX, has parasympathetic fibers that innervate the parotid salivary gland. The
preganglionic fibers depart CNIX as the tympanic nerve and continue to the middle ear where they make up a
tympanic plexus on the cochlear promontory of the mesotympanum. The tympanic plexus of nerves rejoin and
form the lesser petrosal nerve and exit through the foramen ovale to synapse at the otic ganglion. From the otic
ganglion postganglionic parasympathetic fibers travel with the auriculotemporal nerve (mandibular branch of
trigeminal, CN V3) to the parotid salivary gland.
The vagus nerve, named from the Latin word vagus means literally "Wandering", since the nerve controls such
a broad range of target tissues, has PSN that originate in the dorsal nucleus of the vagus nerve and
the nucleus ambiguus in the CNS. The vagus nerve is an unusual cranial PSN in that it doesn't join the
trigeminal nerve in order to get to its target tissues. Another peculiarity is that the vagus has an autonomic
ganglion associated with it at approximately the level of C1 vertebra. The vagus gives no PSN to the cranium.
The vagus nerve is hard to track definitively due to its ubiquitous nature in the thorax and abdomen so the
major contributions will be discussed. Several PSN nerves come off the vagus nerve as it enters the thorax.
One nerve is the recurrent laryngeal nerve, which becomes the inferior laryngeal nerve. From the left vagus
nerve the recurrent laryngeal nerve hooks around the aorta to travel back up to the larynx and
proximal esophaguswhile, from the right vagus nerve, the recurrent laryngeal nerve hooks around the
right subclavian artery to travel back up to the same location as its counterpart. These different paths are a
direct result of embryological development of the circulatory system. Each recurrent laryngeal nerve supplies
the trachea and the esophagus with parasympathetic secretomotor innervation for glands associated with them
(and other fibers that are not PSN).
Another nerve that comes off the vagal nerves approximately at the level of entering the thorax are the cardiac
nerves. These cardiac nerves go on to form cardiac and pulmonary plexuses around the heart and lungs. As
the main vagus nerves continue into the thorax they become intimately linked with the esophagus and
sympathetic nerves from the sympathetic trunks to form the esophageal plexus. This is very efficient as the
major function of the vagus nerve from there on will be control of the gut smooth muscles and glands. As
the esophageal plexus enter the abdomen through the esophageal hiatus anterior and posterior vagal trunks
form. The vagal trunks then join with preaortic sympathetic ganglion around the aorta to disperse with the blood
vessels and sympathetic nerves throughout the abdomen. The extent of the PSN in the abdomen include
the pancreas, kidneys, liver, gall bladder, stomach and gut tube. The vagal contribution of PSN continues down
the gut tube until the end of the midgut. The midgut ends 2/3 of the way across the transverse colon near
the splenic flexure.
Pelvic Splanchnic Control
The pelvic splanchnic nerves, S2-4, work in tandem to innervate the pelvic viscera. Unlike in the cranium,
where one PSN was in charge of one particular tissue or region, for the most part the pelvic splanchnics each
contribute fibers to pelvic viscera by first traveling to one or more plexuses before being dispersed to the target
tissue. These plexuses are composed of mixed autonomic nerve fibers (PSN and SN) and include the vesical,
prostatic, rectal, uterovaginal and inferior hypogastric plexus. The preganglionic neurons in the neurons do not
synapse in named ganglion as in the cranium but rather in the walls of the tissues or organs that they
innervate. The fiber paths are variable and each individual's autonomic nervous system in the pelvis is unique.
The visceral tissues in the pelvis that the PSN control include: urinary bladder, ureters, urinary sphincter, anal
sphincter, uterus, prostate, glands, vagina and penis. Unconsciously, the PSN will cause peristaltic movements
of the ureters helping to move urine from the kidneys into the bladder and move feces down the intestinal tract
and upon necessity, the PSN will assist excreting urine from the bladder or defecation. Stimulation of the PSN
will cause the detrusor muscle (urinary bladder wall) to contract and simultaneously relax the internal sphincter
urethrae muscle to relax allowing void of urine. Also, PSN stimulation to the internal anal sphincter will relax
this muscle and allow defecation. There are other skeletal muscles involved with these processes but the PSN
play a huge role in continence.
Another role that the PSN play in the pelvis is in sexual activity. In males, the cavernous nerves from the
prostatic plexus stimulate smooth muscle in the fibrous trabeculae of the coiled helicene arteries to relax and
allow blood to fill the corpora cavernosum and the corpus spongiosum of the penis, making it rigid to prepare
for sexual activity. Upon emission of ejaculate, the sympathetics participate and cause peristalsis of the ductus
deferens and closure of the internal urethral sphincter to prevent semen from entering the bladder. At the same
time, parasympathetics cause peristalsis of the urethral muscle, and the pudendal nerve causes contraction of
the bulbospongiosus (skeletal muscle is not via PSN), to forcibly emit the semen. During remission the penis
becomes flaccid again. In the female, there is erectile tissue analogous to the male yet less substantial that
plays a large role in sexual stimulation. The PSN cause release of secretions in the female that decrease
friction. Also in the female, the parasympathetics innervate the fallopian tubes which helps peristaltic
contractions and movement of the oocyte to the uterus for implantation. The secretions from the female genital
tract aids in semen migration. The PSN (and SN to a lesser extent) play a huge role in reproduction.
Clinical Significance
The parasympathetic nervous system promotes digestion and the synthesis of glycogen, and allows for normal
function and behavior.
Receptors
The parasympathetic nervous system uses chiefly acetylcholine (ACh) as its neurotransmitter, although
other peptides (such ascholecystokinin) may act on the PSNS as a neurotransmitter. The ACh acts on two
types of receptors, the muscarinic and nicotiniccholinergic receptors. Most transmissions occur in two stages:
When stimulated, the preganglionic nerve releases ACh at the ganglion, which acts on nicotinic receptors
of postganglionic neurons. The postganglionic nerve then releases ACh to stimulate the muscarinic receptors
of the target organ.
Cerebellum
Brain: Cerebellum

A human brain, with the cerebellum colored in purple

Drawing of the human brain, showing cerebellum and pons

Part of Metencephalon
Artery SCA, AICA, PICA
Vein superior, inferior
NeuroLex ID birnlex_1489
The cerebellum (Latin for little brain) is a region of the brain that plays an important role inmotor control. It is
also involved in some cognitive functions such as attention and language, and probably in
some emotional functions such as regulating fear and pleasure [Link] movement-related functions are
the most clearly understood, however. The cerebellum does not initiate movement, but it contributes
to coordination, precision, and accurate timing. It receives input from sensory systems and from other parts of
the brain and spinal cord, and integrates these inputs to fine tune motor activity. Because of this fine-tuning
function,damage to the cerebellum does not cause paralysis, but instead produces disorders in fine
movement, equilibrium, posture, and motor learning.
In terms of anatomy, the cerebellum has the appearance of a separate structure attached to the bottom of the
brain, tucked underneath the cerebral hemispheres. The surface of the cerebellum is covered with finely
spaced parallel grooves, in striking contrast to the broad irregular convolutions of the cerebral cortex. These
parallel grooves conceal the fact that the cerebellum is actually a continuous thin layer of neural
tissue (the cerebellar cortex), tightly folded in the style of an accordion. Within this thin layer are several types
of neurons with a highly regular arrangement, the most important being Purkinje cells and granule cells. This
complex neural network gives rise to a massive signal-processing capability, but almost the entirety of its
output is directed to a set of small deep cerebellar nuclei lying in the interior of the cerebellum.
In addition to its direct role in motor control, the cerebellum also is necessary for several types of motor
learning, the most notable one being learning to adjust to changes in sensorimotor relationships. Several
theoretical models have been developed to explain sensorimotor calibration in terms of synaptic
plasticity within the cerebellum. Most of them derive from early models formulated by David Marr and James
Albus, which were motivated by the observation that each cerebellar Purkinje cell receives two dramatically
different types of input: On one hand, thousands of inputs from parallel fibers, each individually very weak; on
the other hand, input from one single climbing fiber, which is, however, so strong that a single climbing fiber
action potential will reliably cause a target Purkinje cell to fire a burst of action potentials. The basic concept of
the Marr-Albus theory is that the climbing fiber serves as a "teaching signal", which induces a long-lasting
change in the strength of synchronously activated parallel fiber inputs. Observations of long-term depression in
parallel fiber inputs have provided support for theories of this type, but their validity remains controversial.
Structure
At the level of large-scale anatomy, the cerebellum consists of a tightly folded and crumpled layer of cortex,
with white matter underneath, several deep nuclei embedded in the white matter, and a fluid-filled ventricle at
the base. At the microscopic level, each part of the cerebellar cortex consists of the same small set of neuronal
elements, laid out with a highly stereotyped geometry. At an intermediate level, the cerebellum and its auxiliary
structures can be decomposed into several hundred or thousand independently functioning modules called
"microzones" or "microcompartments".
Anatomy

Anterior view of the human cerebellum, with numbers indicating salient landmarks
The cerebellum is located at the bottom of the brain, with the large mass of the cerebral cortexabove it and the
portion of the brainstem called the pons in front of it. It is separated from the overlying cerebrum by a layer of
leathery dura mater; all of its connections with other parts of the brain travel through the pons. Anatomists
classify the cerebellum as part of the metencephalon, which also includes the pons; the metencephalon is the
upper part of the rhombencephalon or "hindbrain". Like the cerebral cortex, the cerebellum is divided into two
hemispheres; it also contains a narrow midline zone called the vermis. A set of large folds is, by convention,
used to divide the overall structure into 10 smaller "lobules". Because of its large number of tiny granule cells,
the cerebellum contains more neurons than the rest of the brain put together, but it takes up only 10% of total
brain volume.

Vertical cross-section of the human cerebellum, showing folding pattern of the cortex, and interior structures
The unusual surface appearance of the cerebellum conceals the fact that most of its volume is made up of a
very tightly folded layer of gray matter, the cerebellar cortex. It has been estimated that, if the human cerebellar
cortex were completely unfolded, it would give rise to a layer of neural tissue about 1 meter long and averaging
5 centimeters wide — a total surface area of about 500 square cm, packed within a volume of dimensions 6 cm
× 5 cm × 10 cm. Underneath the gray matter of the cortex lies white matter, made up largely
of myelinated nerve fibers running to and from the cortex. Embedded within the white matter — which is
sometimes called the arbor vitae (Tree of Life) because of its branched, tree-like appearance in cross-section
— are four deep cerebellar nuclei, composed of gray matter.
Subdivisions
Based on surface appearance, three lobes can be distinguished in the cerebellum, called theflocculonodular
lobe, anterior lobe (above the primary fissure), and posterior lobe (below the primary fissure). These lobes
divide the cerebellum from rostral to caudal (in humans, top to bottom). In terms of function, however, there is a
more important distinction along the medial-to-lateral dimension. Leaving out the flocculonodular part, which
has distinct connections and functions, the cerebellum can be parsed functionally into a medial sector called
the spinocerebellum and a larger lateral sector called the cerebrocerebellum. A narrow strip of protruding tissue
along the midline is called the vermis (Latin for "worm").
Cerebellum and surrounding regions; sagittal view of
one hemisphere. A: Midbrain. B: Pons. C: Medulla. Schematic representation of the major anatomical subdivisions of
D: Spinal cord. E:Fourth ventricle. F: Arbor vitae. the cerebellum. Superior view of an "unrolled" cerebellum, placing
G: Tonsil. H: Anterior lobe. I: Posterior lobe. the vermis in one plane.
The smallest region, the flocculonodular lobe, is often called the vestibulocerebellum. It is the oldest part in
evolutionary terms (archicerebellum) and participates mainly in balance and spatial orientation; its primary
connections are with the vestibular nuclei, although it also receives visual and other sensory input. Damage to
it causes disturbances of balance and gait.
The medial zone of the anterior and posterior lobes constitutes the spinocerebellum, also known as
paleocerebellum. This sector of the cerebellum functions mainly to fine-tune body and limb movements. It
receives proprioception input from the dorsal columns of the spinal cord(including the spinocerebellar tract) and
from the trigeminal nerve, as well as from visual and auditory systems. It sends fibres to deep cerebellar nuclei
that, in turn, project to both the cerebral cortex and the brain stem, thus providing modulation of descending
motor systems.
The lateral zone, which in humans is by far the largest part, constitutes the cerebrocerebellum, also known as
neocerebellum. It receives input exclusively from the cerebral cortex (especially the parietal lobe) via
the pontine nuclei (forming cortico-ponto-cerebellar pathways), and sends output mainly to the
ventrolateral thalamus (in turn connected to motor areas of the premotor cortex and primary motor area of the
cerebral cortex) and to the red nucleus. There is disagreement about the best way to describe the functions of
the lateral cerebellum: It is thought to be involved in planning movement that is about to occur, in evaluating
sensory information for action, and in a number of purely cognitive functions as well.
Cellular components

Microcircuitry of the cerebellum. (+): excitatory; (-): inhibitory; MF: Mossy fiber; DCN: Deep cerebellar nuclei; IO: Inferior
olive; CF: Climbing fiber; GC: Granule cell; PF:Parallel fiber; PC: Purkinje cell; GgC: Golgi cell; SC:Stellate cell; BC: Basket
cell
Transverse section of a cerebellar folium, showing principle cell types and connections
Two types of neuron play dominant roles in the cerebellar circuit: Purkinje cells andgranule cells. Three types
of axons also play dominant roles: mossy fibers and climbing fibers (which enter the cerebellum from outside),
and parallel fibers (which are the axons of granule cells). There are two main pathways through the cerebellar
circuit, originating from mossy fibers and climbing fibers, both terminating in the deep cerebellar nuclei.
Mossy fibers project directly to the deep nuclei, but also give rise to the pathway: mossy fiber → granule cells
→ parallel fibers → Purkinje cells → deep nuclei. Climbing fibers project to Purkinje cells and also send
collaterals directly to the deep nuclei. The mossy fiber and climbing fiber inputs each carry fiber-specific
information; the cerebellum also receives dopaminergic, serotonergic, noradrenergic, and cholinergic inputs
that presumably perform global modulation.
The cerebellar cortex is divided into three layers. At the bottom lies the thick granular layer, densely packed
with granule cells, along with much smaller numbers of interneurons, mainly Golgi cells. In the middle lies the
Purkinje layer, a narrow zone that contains only the cell bodies of Purkinje cells. At the top lies the molecular
layer, which contains the flattened dendritic trees of Purkinje cells, along with the huge array of parallel fibers
penetrating the Purkinje cell dendritic trees at right angles. This outermost layer of the cerebellar cortex also
contains two types of inhibitory interneurons, stellate cells, and basket cells. Both stellate and basket cells
form GABAergic synapses onto Purkinje cell dendrites.
Purkinje cells
Purkinje cells are among the most distinctive neurons in the brain, and also among the earliest types to be
recognized — they were first described by the Czech anatomist Jan Evangelista Purkyně in 1837. They are
distinguished by the shape of the dendritic tree: The dendrites branch very profusely, but are severely flattened
in a plane perpendicular to the cerebellar folds. Thus, the dendrites of a Purkinje cell form a dense planar net,
through which parallel fibers pass at right angles. The dendrites are covered with dendritic spines, each of
which receives synaptic input from a parallel fiber. Purkinje cells receive more synaptic inputs than any other
type of cell in the brain — estimates of the number of spines on a single human Purkinje cell run as high as
200,000. The large, spherical cell bodies of Purkinje cells are packed into a narrow layer (one cell thick) of the
cerebellar cortex, called thePurkinje layer. After emitting collaterals that innervate nearby parts of the cortex,
their axons travel into the deep cerebellar nuclei, where they make on the order of 1,000 contacts each with
several types of nuclear cells, all within a small domain. Purkinje cells use GABA as their neurotransmitter, and
therefore exert inhibitory effects on their targets.

Drawing of a Purkinje cell from cat cerebellum

Purkinje cells form the heart of the cerebellar circuit, and their large size and distinctive activity patterns have
made it relatively easy to study their response patterns in behaving animals using extracellular recording
techniques. Purkinje cells normally emit action potentials at a high rate even in the absence of synaptic input.
In awake, behaving animals, mean rates averaging around 40 Hz are typical. The spike trains show a mixture
of what are called simple and complex spikes. A simple spike is a single action potential followed by a
refractory period of about 10 msec; a complex spike is a stereotyped sequence of action potentials with very
short inter-spike intervals and declining amplitudes. Physiological studies have shown that complex spikes
(which occur at baseline rates around 1 Hz and never at rates much higher than 10 Hz) are reliably associated
with climbing fiber activation, while simple spikes are produced by a combination of baseline activity and
parallel fiber input. Complex spikes are often followed by a pause of several hundred msec during which simple
spike activity is suppressed.
Granule cells
Cerebellar granule cells, in contrast to Purkinje cells, are among the smallest neurons in the brain. They are
also easily the most numerous neurons in the brain: In humans, estimates of their total number average around
50 billion, which means that about 3/4 of the brain's neurons are cerebellar granule cells. Their cell bodies are
packed into a thick layer at the bottom of the cerebellar cortex. A granule cell emits only four to five dendrites,
each of which ends in an enlargement called a dendritic claw. These enlargements are sites of excitatory input
from mossy fibers and inhibitory input from Golgi cells.

Granule cells, parallel fibers, and Purkinje cells with flattened dendritic trees
The thin, unmyelinated axons of granule cells rise vertically to the upper (molecular) layer of the cortex, where
they split in two, with each branch traveling horizontally to form a parallel fiber; the splitting of the vertical
branch into two horizontal branches gives rise to a distinctive "T" shape. A parallel fiber runs for an average of
3 mm in each direction from the split, for a total length of about 6 mm (about 1/10 of the total width of the
cortical layer). As they run along, the parallel fibers pass through the dendritic trees of Purkinje cells, contacting
one of every 3–5 that they pass, making a total of 80–100 synaptic connections with Purkinje cell dendritic
spines. Granule cells use glutamate as their neurotransmitter, and therefore exert excitatory effects on their
targets.
Granule cells receive all of their input from mossy fibers, but outnumber them 200 to 1 (in humans). Thus, the
information in the granule cell population activity state is the same as the information in the mossy fibers, but
recoded in a much more expansive way. Because granule cells are so small and so densely packed, it has
been very difficult to record their spike activity in behaving animals, so there is little data to use as a basis of
theorizing. The most popular concept of their function was proposed by David Marr, who suggested that they
could encode combinations of mossy fiber inputs. The idea is that with each granule cell receiving input from
only 4–5 mossy fibers, a granule cell would not respond if only a single one of its inputs were active, but would
respond if more than one were active. This combinatorial coding scheme would potentially allow the cerebellum
to make much finer distinctions between input patterns than the mossy fibers alone would permit.
Mossy fibers
Mossy fibers enter the granular layer from their points of origin, many arising from the pontine nuclei, others
from the spinal cord, vestibular nuclei, etc. In the human cerebellum, the total number of mossy fibers has been
estimated at about 200 million. These fibers form excitatory synapses with the granule cells and the cells of the
deep cerebellar nuclei. Within the granular layer, a mossy fiber generates a series of enlargements
called rosettes. The contacts between mossy fibers and granule cell dendrites take place within structures
calledglomeruli. Each glomerulus has a mossy fiber rosette at its center, and up to 20 granule cell dendritic
claws contacting it. Terminals fromGolgi cells infiltrate the structure and make inhibitory synapses onto the
granule cell dendrites. The entire assemblage is surrounded by a sheath of glial cells. Each mossy fiber sends
collateral branches to several cerebellar folia, generating a total of 20–30 rosettes; thus a single mossy fiber
makes contact with an estimated 400–600 granule cells.
Climbing fibers
Purkinje cells also receive input from the inferior olivary nucleus (IO) on the contralateral side of the brainstem,
via climbing fibers. Although the IO lies in the medulla oblongata, and receives input from the spinal cord,
brainstem, and cerebral cortex, its output goes entirely to the cerebellum. A climbing fiber gives off collaterals
to the deep cerebellar nuclei before entering the cerebellar cortex, where it splits into about 10 terminal
branches, each of which innervates a single Purkinje cell. In striking contrast to the 100,000-plus inputs from
parallel fibers, each Purkinje cell receives input from exactly one climbing fiber; but this single fiber "climbs" the
dendrites of the Purkinje cell, winding around them and making a total of up to 300 synapses as it goes. The
net input is so strong that a single action potential from a climbing fiber is capable of producing an extended
complex spike in the Purkinje cell: a burst of several spikes in a row, with diminishing amplitude, followed by a
pause during which activity is suppressed. The climbing fiber synapses cover the cell body and proximal
dendrites; this zone is devoid of parallel fiber inputs.
Climbing fibers fire at low rates, but a single climbing fiber action potential induces a burst of several action
potentials in a target Purkinje cell (a complex spike). The contrast between parallel fiber and climbing fiber
inputs to Purkinje cells (over 100,000 of one type versus exactly one of the other type) is perhaps the most
provocative feature of cerebellar anatomy, and has motivated much of the theorizing. In fact, the function of
climbing fibers is the most controversial topic concerning the cerebellum. There are two schools of thought, one
following Marr and Albus in holding that climbing fiber input serves primarily as a teaching signal, the other
holding that its function is to shape cerebellar output directly. Both views have been defended in great length in
numerous publications. In the words of one review, "In trying to synthesize the various hypotheses on the
function of the climbing fibers, one has the sense of looking at a drawing by Escher. Each point of view seems
to account for a certain collection of findings, but when one attempts to put the different views together, a
coherent picture of what the climbing fibers are doing does not appear. For the majority of researchers, the
climbing fibers signal errors in motor performance, either in the usual manner of discharge frequency
modulation or as a single announcement of an 'unexpected event'. For other investigators, the message lies in
the degree of ensemble synchrony and rhythmicity among a population of climbing fibers."
Deep nuclei

Cross-section of human cerebellum, showing the dentate nucleus, as well as the pons and inferior olivary nucleus
The deep nuclei of the cerebellum are clusters of gray matter lying within the white matter at the core of the
cerebellum. They are, with the minor exception of the nearby vestibular nuclei, the sole sources of output from
the cerebellum. These nuclei receive collateral projections from mossy fibers and climbing fibers, as well as
inhibitory input from the Purkinje cells of the cerebellar cortex. The three nuclei (dentate, interpositus, and
fastigial) each communicate with different parts of the brain and cerebellar cortex. The fastigial and interpositus
nuclei belong to the spinocerebellum. The dentate nucleus, which in mammals is much larger than the others,
is formed as a thin, convoluted layer of gray matter, and communicates exclusively with the lateral parts of the
cerebellar cortex. The flocculonodular lobe is the only part of the cerebellar cortex that does not project to the
deep nuclei — its output goes to the vestibular nuclei instead.
The majority of neurons in the deep nuclei have large cell bodies and spherical dendritic trees with a radius of
about 400 μm, and use glutamate as their neurotransmitter. These cells project to a variety of targets outside
the cerebellum. Intermixed with them is a lesser number of small cells, which use GABA as neurotransmitter
and project exclusively to the inferior olivary nucleus, the source of climbing fibers. Thus, the nucleo-olivary
projection provides an inhibitory feedback to match the excitatory projection of climbing fibers to the nuclei.
There is evidence that each small cluster of nuclear cells projects to the same cluster of olivary cells that send
climbing fibers to it; there is strong and matching topography in both directions.
When a Purkinje cell axon enters one of the deep nuclei, it branches to make contact with both large and small
nuclear cells, but the total number of cells contacted is only about 35 (in cats). On the converse, a single deep
nuclear cell receives input from approximately 860 Purkinje cells (again in cats).
Compartmentalization
Schematic illustration of the structure of zones and microzones in the cerebellar cortex
From the viewpoint of gross anatomy, the cerebellar cortex appears to be a homogeneous sheet of tissue, and,
from the viewpoint of microanatomy, all parts of this sheet appear to have the same internal structure. There
are, however, a number of respects in which the structure of the cerebellum is compartmentalized. There are
large compartments that are generally known as zones; these can be decomposed into smaller compartments
known asmicrozones.
The first indications of compartmental structure came from studies of the receptive fields of cells in various
parts of the cerebellum cortex. Each body part maps to specific points in the cerebellum, but there are
numerous repetitions of the basic map, forming an arrangement that has been called "fractured somatotopy". A
clearer indication of compartmentalization is obtained by immunostaining the cerebellum for certain types of
protein. The best-known of these markers are called "zebrins", because staining for them gives rise to a
complex pattern reminiscent of the stripes on a zebra. The stripes generated by zebrins and other
compartmentalization markers are oriented perpendicular to the cerebellar folds — that is, they are narrow in
the mediolateral direction, but much more extended in the longitudinal direction. Different markers generate
different sets of stripes, and the widths and lengths vary as a function of location, but they all have the same
general shape.
Oscarsson in the late 1970s proposed that these cortical zones can be partitioned into smaller units called
microzones. A microzone is defined as a group of Purkinje cells all having the same somatotopic receptive
field. Microzones were found to contain on the order of 1000 Purkinje cells each, arranged in a long, narrow
strip, oriented perpendicular to the cortical folds. Thus, as the adjoining diagram illustrates, Purkinje cell
dendrites are flattened in the same direction as the microzones extend, while parallel fibers cross them at right
angles.
It is not only receptive fields that define the microzone structure: The climbing fiber input from the inferior
olivary nucleus is equally important. The branches of a climbing fiber (usually numbering about 10) usually
innervate Purkinje cells belonging to the same microzone. Moreover, olivary neurons that send climbing fibers
to the same microzone tend to be coupled by gap junctions, which synchronize their activity, causing Purkinje
cells within a microzone to show correlated complex spike activity on a millisecond time scale. Also, the
Purkinje cells belonging to a microzone all send their axons to the same small cluster of output cells within
the deep cerebellar nuclei. Finally, the axons of basket cells are much longer in the longitudinal direction than
in the mediolateral direction, causing them to be confined largely to a single microzone. The consequence of all
this structure is that cellular interactions within a microzone are much stronger than interactions between
different microzones.
In 2005, Richard Apps and Martin Garwicz summarized evidence that microzones themselves form part of a
larger entity they call a multizonal microcomplex. Such a microcomplex includes several spatially separated
cortical microzones, all of which project to the same group of deep cerebellar neurons, plus a group of coupled
olivary neurons that project to all of the included microzones as well as to the deep nuclear area.
Function
The strongest clues to the function of the cerebellum have come from examining the consequences of damage
to it. Animals and humans with cerebellar dysfunction show, above all, problems with motor control. They
continue to be able to generate motor activity, but it loses precision, producing erratic, uncoordinated, or
incorrectly timed movements. A standard test of cerebellar function is to reach with the tip of the finger for a
target at arm's length: A healthy person will move the fingertip in a rapid straight trajectory, whereas a person
with cerebellar damage will reach slowly and erratically, with many mid-course corrections. Deficits in non-
motor functions are more difficult to detect. Thus, the general conclusion reached decades ago is that the basic
function of the cerebellum is not to initiate movements, or to decide which movements to execute, but rather to
calibrate the detailed form of a movement.
Prior to the 1990s, the function of the cerebellum was almost universally believed to be purely motor-related,
but newer findings have brought that view strongly into question. Functional imaging studies have shown
cerebellar activation in relation to language, attention, and mental imagery; correlation studies have shown
interactions between the cerebellum and non-motoric areas of the cerebral cortex; and a variety of non-motor
symptoms have been recognized in people with damage that appears to be confined to the cerebellum.
Kenji Doya has argued that the function of the cerebellum is best understood not in terms of what behaviors it
is involved in but rather in terms of what neural computations it performs; the cerebellum consists of a large
number of more or less independent modules, all with the same geometrically regular internal structure, and
therefore all, it is presumed, performing the same computation. If the input and output connections of a module
are with motor areas (as many are), then the module will be involved in motor behavior; but, if the connections
are with areas involved in non-motor cognition, the module will show other types of behavioral correlates. The
cerebellum, Doya proposes, is best understood as a device for supervised learning, in contrast to the basal
ganglia, which perform reinforcement learning, and the cerebral cortex, which performs unsupervised learning.
Principles
The comparative simplicity and regularity of the cerebellar anatomy led to an early hope that it might imply a
similar simplicity of computational function, as expressed in one of the first books on cerebellar
electrophysiology, The Cerebellum as a Neuronal Machine byJohn C. Eccles, Masao Ito, and Janos
Szentágothai. Although a full understanding of cerebellar function has remained elusive, at least four principles
have been identified as important: (1) feedforward processing, (2) divergence and convergence, (3) modularity,
and (4) plasticity.
1. Feedforward processing: The cerebellum differs from most other parts of the brain (especially the cerebral
cortex) in that the signal processing is almost entirely feedforward - that is, signals move unidirectionally
through the system from input to output, with very little recurrent internal transmission. The small amount of
recurrence that does exist consists of mutual inhibition; there are no mutually excitatory circuits. This
feedforward mode of operation means that the cerebellum, in contrast to the cerebral cortex, cannot generate
self-sustaining patterns of neural activity. Signals enter the circuit, are processed by each stage in sequential
order, and then leave. As Eccles, Ito, and Szentágothai wrote, "This elimination in the design of all possibility of
reverberatory chains of neuronal excitation is undoubtedly a great advantage in the performance of the
cerebellum as a computer, because what the rest of the nervous system requires from the cerebellum is
presumably not some output expressing the operation of complex reverberatory circuits in the cerebellum but
rather a quick and clear response to the input of any particular set of information."
2. Divergence and convergence: In the human cerebellum, information from 200 million mossy fiber inputs is
expanded to 40 billiongranule cells, whose parallel fiber outputs then converge onto 15 million Purkinje
cells. Because of the way that they are lined up longitudinally, the 1000 or so Purkinje cells belonging to a
microzone may receive input from as many as 100 million parallel fibers, and focus their own output down to a
group of less than 50 deep nuclear cells. Thus, the cerebellar network receives a modest number of inputs,
processes them very extensively through its rigorously structured internal network, and sends out the results
via a very limited number of output cells.
3. Modularity: The cerebellar system is functionally divided into more or less independent modules, which
probably number in the hundreds to thousands. All modules have a similar internal structure, but different
inputs and outputs. A module (a multizonal microcompartment in the terminology of Apps and Garwicz)
consists of a small cluster of neurons in the inferior olivary nucleus, a set of long narrow strips of Purkinje cells
in the cerebellar cortex (microzones), and a small cluster of neurons in one of the deep cerebellar nuclei.
Different modules share input from mossy fibers and parallel fibers, but in other respects they appear to
function independently — the output of one module does not appear to significantly influence the activity of
other modules.
4. Plasticity: The synapses between parallel fibers and Purkinje cells, and the synapses between mossy fibers
and deep nuclear cells, are both susceptible to modification of their strength. In a single cerebellar module,
input from as many as a billion parallel fibers converges onto a group of less than 50 deep nuclear cells, and
the influence of each parallel fiber on those nuclear cells is adjustable. This arrangement gives tremendous
flexibility for fine-tuning the relationship between cerebellar inputs and outputs.
Learning
There is considerable evidence that the cerebellum plays an essential role in some types of motor learning.
The tasks where the cerebellum most clearly comes into play are those in which it is necessary to make fine
adjustments to the way an action is performed. There has, however, been much dispute about whether
learning takes place within the cerebellum itself, or whether it merely serves to provide signals that promote
learning in other brain structures. Most theories that assign learning to the circuitry of the cerebellum are
derived from early ideas of David Marr and James Albus, who postulated that climbing fibers provide a
teaching signal that induces synaptic modification inparallel fiber—Purkinje cell synapses. Marr assumed that
climbing fiber input would cause synchronously activated parallel fiber inputs to be strengthened. Most later
cerebellar-learning models, however, have followed Albus in assuming that climbing fiber activity would be
anerror signal, and would cause synchronously activated parallel fiber inputs to be weakened. Some of these
later models, such as theAdaptive Filter model of Fujita made attempts to understand cerebellar function in
terms of optimal control theory.
The idea that climbing fiber activity functions as an error signal has been examined in many experimental
studies, with some supporting it but others casting doubt. In a pioneering study by Gilbert and Thach from
1977, Purkinje cells from monkeys learning a reaching task showed increased complex spike activity — which
is known to reliably indicate activity of the cell's climbing fiber input — during periods when performance was
poor. Several studies of motor learning in cats observed complex spike activity when there was a mismatch
between an intended movement and the movement that was actually executed. Studies of the vestibulo-ocular
reflex (which stabilizes the visual image on the retina when the head turns) found that climbing fiber activity
indicated "retinal slip", although not in a very straightforward way.
One of the most extensively studied cerebellar learning tasks is the eyeblink conditioning paradigm, in which a
neutral conditioned stimulus such as a tone or a light is repeatedly paired with an unconditioned stimulus, such
as an air puff, that elicits a blink response. After such repeated presentations of the CS and US, the CS will
eventually elicit a blink before the US, a conditioned response or CR. Experiments showed that lesions
localized either to a specific part of the interpositus nucleus (one of the deep cerebellar nuclei or to a few
specific points in the cerebellar cortex would abolish learning of a correctly timed blink response. If cerebellar
outputs are pharmacologically inactivated while leaving the inputs and intracellular circuits intact, learning takes
place even while the animal fails to show any response, whereas, if intracerebellar circuits are disrupted, no
learning takes place — these facts taken together make a strong case that the learning, indeed, occurs inside
the cerebellum.
Theories and computational models

Model of a cerebellar perceptron, as formulated by James Albus

The large base of knowledge about the anatomical structure and behavioral functions of the cerebellum have
made it a fertile ground for theorizing — there are perhaps more theories of the function of the cerebellum than
of any other part of the brain. The most basic distinction among them is between "learning theories" and
"performance theories" — that is, theories that make use of synaptic plasticity within the cerebellum to account
for its role in learning, versus theories that account for aspects of ongoing behavior on the basis of cerebellar
signal processing. Several theories of both types have been formulated as mathematical models and simulated
using computers.
Perhaps the earliest "performance" theory was the "delay line" hypothesis of Valentino Braitenberg. The
original theory put forth by Braitenberg and Atwood in 1958 proposed that slow propagation of signals along
parallel fibers imposes predictable delays that allow the cerebellum to detect time relationships within a certain
window. Experimental data did not support the original form of the theory, but Braitenberg continued to argue
for modified versions. The hypothesis that the cerebellum functions essentially as a timing system has also
been advocated by Richard Ivry. Another influential "performance" theory is the Tensor Network Theory of
Pellionisz and Llinás, which provided an advanced mathematical formulation of the idea that the fundamental
computation performed by the cerebellum is to transform sensory into motor coordinates.
Theories in the "learning" category almost all derive from early publications by David Marr and James
Albus. Marr's 1969 paper proposed that the cerebellum is a device for learning to associate elemental
movements encoded by climbing fibers with mossy fiber inputs that encode the sensory context. Albus
proposed that a cerebellar Purkinje cell functions as a perceptron, a neurally inspired abstract learning device.
The most basic difference between the Marr and Albus theories is that Marr assumed that climbing fiber activity
would cause parallel fiber synapses to be strengthened, whereas Albus proposed that they would be
weakened. Albus also formulated his version as a software algorithm he called a CMAC (Cerebellar Model
Articulation Controller), which has been tested in a number of applications.
Pathology

Altered walking gait of a woman with cerebellar disease

The most salient symptoms of cerebellar dysfunction are motor-related — the specific symptoms depend on
which part of the cerebellum is involved and how it is disrupted. Damage to the flocculonodular lobe
(the vestibular part) may show up as a loss of equilibrium and, in particular, an altered walking gait, with a wide
stance that indicates difficulty in balancing. Damage to the midline portion may disrupt whole-body movements,
whereas damage localized more laterally is more likely to disrupt fine movements of the hands or limbs.
Damage to the upper part of the cerebellum tends to cause gait impairments and other problems with leg
coordination; damage to the lower part is more likely to cause uncoordinated or poorly aimed movements of the
arms and hands, as well as difficulties in speed. This complex of motor symptoms is called "ataxia". To identify
cerebellar problems, the neurological examination includes assessment of gait (a broad-based gait being
indicative of ataxia), finger-pointing tests and assessment of posture. If cerebellar dysfunction is indicated,
a magnetic resonance imaging scan can be used to obtain a detailed picture of any structural alterations that
may exist.

The lower trace shows an attempt by a patient with cerebellar disease to reproduce the upper trace.
The list of medical problems that can produce cerebellar damage is long: it includes stroke; hemorrhage;
tumors; alcoholism; physical trauma such as gunshot wounds; and chronic degenerative conditions such
as olivopontocerebellar atrophy. Some forms of migraine headache may also produce temporary dysfunction of
the cerebellum, of variable severity.
Aging
The human cerebellum changes with age. These changes may differ from those of other parts of the brain, for
example the gene expression pattern in the human cerebellum shows less age-related alteration than in
the cerebral cortex. Some studies have reported reductions in numbers of cells or volume of tissue, but the
amount of data relating to this question is not very large.
Ataxia
Ataxia (from Greek α- [used as a negative prefix] + -τάξις [order], meaning "lack of order") is
a neurological sign and symptom that consists of gross lack of coordination of muscle movements. Ataxia is a
non-specific clinical manifestation implying dysfunction of the parts of thenervous system that coordinate
movement, such as the cerebellum. Several possible causes exist for these patterns of neurological
dysfunction. The term "dystaxia" is a rarely-used synonym.
The International Ataxia Awareness Day is observed on September 25 each year.
Types
Cerebellar
The term cerebellar ataxia is employed to indicate ataxia that is due to dysfunction of the cerebellum. This
causes a variety of elementary neurological deficits, such as
antagonist hypotonia, asynergy, dysmetria, dyschronometria, and dysdiadochokinesia. How and where these
abnormalities manifest themselves depends on which cerebellar structures have been damaged, and whether
the lesion is bilateral or unilateral.
 Dysfunction of the vestibulocerebellum impairs the balance and the control of eye movements.
This presents itself with postural instability, in which the person tends to separate his/her feet upon
standing, in order to gain a wider base and to avoid bodily oscillations (especially forward-backward ones).
The instability is therefore worsened when standing with the feet together, regardless of whether the eyes
are open or closed. This is a negative Romberg's test], or more accurately, it denotes the individual's
inability to carry out the test, because the individual feels unstable even with open eyes).
 Dysfunction of the spinocerebellum presents itself with a wide-based "drunken sailor" gait,
characterised by uncertain start and stop, lateral deviations, and unequal steps. This part of the cerebellum
regulates body and limb movements.
 Dysfunction of the cerebrocerebellum presents with disturbances in carrying out voluntary, planned
movements. These include:
 intention tremor (coarse trembling, accentuated over the execution of voluntary movements,
possibly involving the head and eyes as well as the limbs and torso);
 peculiar writing abnormalities (large, unequal letters, irregular underlining);
 a peculiar pattern of dysarthria (slurred speech, sometimes characterised by explosive
variations in voice intensity despite a regular rhythm).
Sensory
The term sensory ataxia is employed to indicate ataxia due to loss of proprioception - the loss of sensitivity to
the positions of joint and body parts. This is generally caused by dysfunction of the dorsal columns of the spinal
cord, because they carry proprioceptive information up to the brain. In some cases, the cause of sensory ataxia
may instead be dysfunction of the various parts of the brain which receive positional information, including the
cerebellum, thalamus, and parietal lobes.
Sensory ataxia presents itself with an unsteady "stomping" gait with heavy heel strikes, as well as a postural
instability that is usually worsened when the lack of proprioceptive input cannot be compensated for by visual
input, such as in poorly lit environments.
Physicians can find evidence of sensory ataxia during physical examination by having the patient stand with
his/her feet together and eyesshut. In affected patients, this will cause the instability to worsen markedly,
producing wide oscillations and possibly a fall. This is called a positive Romberg's test. Worsening of the finger-
pointing test with the eyes closed is another feature of sensory ataxia. Also, when the patient is standing with
arms and hands extended toward the physician, if the eyes are closed, the patient's finger will tend to "fall
down" and then be restored to the horizontal extended position by sudden muscular contractions (the "ataxic
hand").
Vestibular
The term vestibular ataxia is employed to indicate ataxia due to dysfunction of the vestibular system, which in
acute and unilateral cases is associated with prominent vertigo, nausea and vomiting. In slow-onset, chronic
bilateral cases of vestibular dysfunction, these characteristic manifestations may be absent,
and dysequilibrium may be the sole presentation.
Causes
The three types of ataxia have overlapping causes, and therefore can either coexist or occur in isolation.
Focal lesions
Any type of focal lesion of the central nervous system (such as stroke, brain tumour, multiple sclerosis) will
cause the type of ataxia corresponding to the site of the lesion: cerebellar if in the cerebellum, sensory if in the
dorsal spinal cord (and rarely in the thalamus orparietal lobe), vestibular if in the vestibular system (including
the vestibular areas of the cerebral cortex).
Exogenous substances
Exogenous substances that cause ataxia mainly do so because they have a depressant effect on central
nervous system function. The most common example is ethanol, that is, alcohol, which is capable of causing
reversible cerebellar and vestibular ataxia. Other examples include various prescription drugs (e.g.
most antiepileptic drugs have cerebellar ataxia as a possible adverse effect), Lithium level over
1.5mEq/L,cannabis ingestion and various other recreational drugs (e.g. ketamine, PCP or dextromethorphan,
all of which are NMDA receptor antagonists that produce a dissociative state at high doses). Exposure to high
levels of methylmercury, through consumption of fish with high mercury concentrations, is also a known cause
of ataxia and other neurological disorders
Vitamin B12 deficiency
Vitamin B12 deficiency may cause, among several neurological abnormalities, overlapping cerebellar and
sensory ataxia.
Causes of isolated sensory ataxia
Peripheral neuropathies may cause generalised or localised sensory ataxia (e.g. a limb only) depending on the
extent of the neuropathic involvement. Spinal disorders of various types may cause sensory ataxia from the
lesioned level below, when they involve the dorsal columns.
Non-hereditary cerebellar degeneration
Non-hereditary causes of cerebellar degeneration include chronic ethanol abuse, paraneoplastic cerebellar
degeneration, high altitude cerebral oedema, coeliac disease, normal pressure hydrocephalus and cerebellitis.
Hereditary ataxias
Ataxia may depend on hereditary disorders consisting of degeneration of the cerebellum and/or of the spine;
most cases feature both to some extent, and therefore present with overlapping cerebellar and sensory ataxia,
even though one is often more evident than the other. Hereditary disorders causing ataxia include autosomal
dominant ones such as spinocerebellar ataxia, episodic ataxia, anddentatorubropallidoluysian atrophy, as well
as autosomal recessive disorders such as Friedreich's ataxia (sensory and cerebellar, with the former
predominating) and Niemann Pick disease, ataxia-telangiectasia (sensory and cerebellar, with the latter
predominating), andabetalipoproteinaemia. An example of X-linked ataxic condition is the rare fragile X-
associated tremor/ataxia syndrome.
Arnold-Chiari Malformation
Arnold-Chiari malformation is a malformation of the brain. It consists of a downward displacement of
the cerebellar tonsils and the medullathrough the foramen magnum, sometimes causing hydrocephalus as a
result of obstruction of cerebrospinal fluid outflow.
Treatment
The movement disorders related to ataxia are primarily treated with physical therapy. As ataxia involves a loss
of coordinated and efficient action of stabilising muscles in the trunk, exercise training typically includes a focus
on stability exercise. There is often an array of other motor deficits requiring exercise treatment including
weakness, balance impairment and decreased endurance. It is also possible that treatment will include
strategies to manage difficulties with everyday activities, such as a cane or walker to decrease the risk of falls
associated with a balance impairment, or prescription of a wheelchair.
Aphasia
Aphasia from the Greek root word "aphatos", meaning speechless, is an acquired language disorder in which
there is an impairment of any language modality. This may include difficulty in producing or comprehending
spoken or written language.
Traditionally, aphasia suggests the total impairment of language ability, and dysphasia a degree of impairment
less than total. However, the term dysphasia is commonly confused withdysphagia, a swallowing disorder, and
thus aphasia has come to mean both partial and total language impairment in common use.
Depending on the area and extent of brain damage, someone suffering from aphasia may be able to speak but
not write, or vice versa, or display any of a wide variety of other deficiencies in language comprehension and
production, such as being able to sing but not speak. Aphasia may co-occur with speech disorders such
as dysarthria or apraxia of speech, which also result from brain damage.
Aphasia can be assessed in a variety of ways, from quick clinical screening at the bedside to several-hour-long
batteries of tasks that examine the key components of language and communication. The prognosis of those
with aphasia varies widely, and is dependent upon age of the patient, site and size of lesion, and type of
aphasia.
Classification
Classifying the different subtypes of aphasia is difficult and has led to disagreements among experts. The
localizationist model is the original model, but modern anatomical techniques and analyses have shown that
precise connections between brain regions and symptom classification don't exist. The neural organization of
language is complicated; language is a comprehensive and complex behavior and it makes sense that it isn't
the product of some small, circumscribed region of the brain.
No classification of patients in subtypes and groups of subtypes is adequate. Only about 60% of patients will fit
in a classification scheme such as fluent/nonfluent/pure aphasias. There is a huge variation among patients
with the same diagnosis, and aphasias can be highly selective. For instance, patients with naming deficits
(anomic aphasia) might show an inability only for naming buildings, or people, or colors.
Localizationist model

Cortex
The localizationist model attempts to classify the aphasia by major characteristics and then link these to areas
of the brain in which the damage has been caused. The initial two categories here were devised by early
neurologists working in the field, namely Paul Broca and Carl Wernicke. Other researchers have added to the
model, resulting in it often being referred to as the "Boston-Neoclassical Model". The most prominent writers on
this topic have been Harold Goodglass andEdith Kaplan.
 Individuals with Broca's aphasia (also termed expressive aphasia) were once thought to have ventral
temporal damage, though more recent work by Dr. Nina Dronkers using imaging and 'lesion analysis' has
revealed that patients with Broca's aphasia have lesions to the medial insular cortex. Broca missed these
lesions because his studies did not dissect the brains of diseased patients, so only the more temporal
damage was visible. Dronkers and Dr. Odile Plaisant scanned Broca's original patients' brains using a non-
invasive MRI scanner to take a closer look. Individuals with Broca's aphasia often have right-sided
weakness or paralysis of the arm and leg, because the frontal lobe is also important for body movement.
 In contrast to Broca's aphasia, damage to the temporal lobe may result in a fluent aphasia that is
called Wernicke's aphasia (also termedsensory aphasia). These individuals usually have no body
weakness, because their brain injury is not near the parts of the brain that control movement.
 Working from Wernicke's model of aphasia, Ludwig Lichtheim proposed five other types of aphasia,
but these were not tested against real patients until modern imaging made more indepth studies available.
The other five types of aphasia in the localizationist model are:
1. Pure word deafness
2. Conduction aphasia
3. Apraxia of speech, which is now considered a separate disorder in itself.
4. Transcortical motor aphasia
5. Transcortical sensory aphasia
 Anomia is another type of aphasia proposed under what is commonly known as the Boston-
Neoclassical model, which is essentially a difficulty with naming. A final type of aphasia, global aphasia,
results from damage to extensive portions of the perisylvian region of the brain.
Other ways to Classify Aphasia
Fluent, non-fluent and "pure" aphasias
The different types of aphasia can be divided into three categories: fluent, non-fluent and "pure" aphasias.
 Fluent aphasias, also called receptive aphasias, are impairments related mostly to the input or
reception of language, with difficulties either in auditory verbal comprehension or in the repetition of words,
phrases, or sentences spoken by others. Speech is easy and fluent, but there are difficulties related to the
output of language as well, such as paraphasia. Examples of fluent aphasias are: Wernicke's
aphasia, Transcortical sensory aphasia, Conduction aphasia, Anomic aphasia
 Nonfluent aphasias, also called expressive aphasias are difficulties in articulating, but in most cases
there is relatively good auditory verbal comprehension. Examples of nonfluent aphasias are: Broca's
aphasia, Transcortical motor aphasia, Global aphasia
 "Pure" aphasias are selective impairments in reading, writing, or the recognition of words. These
disorders may be quite selective. For example, a person is able to read but not write, or is able to write but
not read. Examples of pure aphasias are: Pure alexia, Agraphia,Pure word deafness
Primary and secondary aphasia
Aphasia can be divided into primary and secondary aphasia.
 Primary aphasia is due to problems with language-processing mechanisms.
 Secondary aphasia is the result of other problems, like memory impairments, attention disorders, or
perceptual problems.
Cognitive neuropsychological model
The cognitive neuropsychological model builds on cognitive neuropsychology. It assumes that language
processing can be broken down into a number of modules, each of which has a specific function. Hence there
is a module which recognises phonemes as they are spoken and a module which stores formulated phonemes
before they are spoken. Use of this model clinically involves conducting a battery of assessments (usually from
the PALPA), each of which tests one or a number of these modules. Once a diagnosis is reached as to where
the impairment lies, therapy can proceed to treat the individual module.
Signs and symptoms
People with aphasia may experience any of the following behaviors due to an acquired brain injury, although
some of these symptoms may be due to related or concomitant problems such as dysarthria or apraxia and not
primarily due to aphasia.
 inability to comprehend language
 inability to pronounce, not due to muscle paralysis or weakness
 inability to speak spontaneously
 inability to form words
 inability to name objects
 poor enunciation
 excessive creation and use of personal neologisms
 inability to repeat a phrase
 persistent repetition of phrases
 paraphasia (substituting letters, syllables or words)
 agrammatism (inability to speak in a grammatically correct fashion)
 dysprosody (alterations in inflexion, stress, and rhythm)
 incompleted sentences
 inability to read
 inability to write
 limited verbal output
 difficulty in naming
The following table summarizes some major characteristics of different types of aphasia:
Type of Auditory
Repetition Naming Fluency Presentation
aphasia comprehension
Wernicke's mild–mod mild– defective fluent Individuals with Wernicke's
aphasia severe paraphasic aphasia may speak in long
sentences that have no
meaning, add unnecessary
words, and even create new
"words" (neologisms). For
example, someone with
Wernicke's aphasia may say,
"You know that smoodle
 pinkered and that I want to get
him round and take care of him
like you want before", meaning
"The dog needs to go out so I
will take him for a walk". They
have poor auditory and reading
comprehension, and fluent, but
nonsensical, oral and written
expression. Individuals with
Wernicke's aphasia usually have
great difficulty understanding the
speech of both themselves and
others and are therefore often
unaware of their mistakes.
Transcortical Similar deficits as in Wernicke's
mod–
sensory good poor fluent aphasia, but repetition ability
severe
aphasia remains intact.
Conduction aphasia is caused
by deficits in the connections
between the speech-
comprehension and speech-
production areas. This might be
damage to the arcuate
fasciculus, the structure that
transmits information between
Conduction
poor poor relatively good fluent Wernicke's area and Broca's
aphasia
area. Similar symptoms,
however, can be present after
damage to the insula or to
the auditory cortex. Auditory
comprehension is near normal,
and oral expression is fluent
with occasional paraphasic
errors. Repetition ability is poor.
Anomic aphasia, is essentially a
difficulty with naming. The
patient may have difficulties
naming certain words, linked by
their grammatical type (e.g.
difficulty naming verbs and not
nouns) or by
Nominal or
mod– their semanticcategory (e.g.
Anomic mild mild fluent
severe difficulty naming words relating
aphasia
to photography but nothing else)
or a more general naming
difficulty. Patients tend to
produce grammatic, yet empty,
speech. Auditory
comprehension tends to be
preserved.
Broca's mod–severe mod– mild difficulty non-fluent, Individuals with Broca's aphasia
aphasia severe effortful, frequently speak short,
slow meaningful phrases that are
produced with great effort.
Broca's aphasia is thus
characterized as a nonfluent
aphasia. Affected people often
omit small words such as "is",
"and", and "the". For example, a
person with Broca's aphasia
 may say, "Walk dog" which
could mean "I will take the dog
for a walk", "You take the dog
for a walk" or even "The dog
walked out of the yard".
Individuals with Broca's aphasia
are able to understand the
speech of others to varying
degrees. Because of this, they
are often aware of their
difficulties and can become
easily frustrated by their
speaking problems. It is
associated with
right hemiparesis, meaning that
there can be paralysis of the
patient's right face and arm.
Similar deficits as Broca's
aphasia, except repetition ability
remains intact. Auditory
comprehension is generally fine
Transcortical for simple conversations, but
mild–
motor good mild non-fluent declines rapidly for more
severe
aphasia complex conversations. It is
associated with right
hemiparesis, meaning that there
can be paralysis of the patient's
right face and arm.
Individuals with global aphasia
have severe communication
difficulties and will be extremely
limited in their ability to speak or
comprehend language. They
Global may be totally nonverbal, and/or
poor poor poor non-fluent
aphasia only use facial expressions and
gestures to communicate. It is
associated with right
hemiparesis, meaning that there
can be paralysis of the patient's
right face and arm.
Mixed Similar deficits as in global
transcortical moderate poor poor non-fluent aphasia, but repetition ability
aphasia remains intact.
Characteristics and symptoms
depend upon the site and size of
Subcortical subcortical lesion. Possible sites
aphasias of lesions include the thalamus,
internal capsule, and basal
ganglia.
Jargon aphasia is a fluent or receptive aphasia in which the patient's speech is incomprehensible, but appears
to make sense to them. Speech is fluent and effortless with intact syntax and grammar, but the patient has
problems with the selection of nouns. They will either replace the desired word with another that sounds or
looks like the original one, or has some other connection, or they will replace it withsounds. Accordingly,
patients with jargon aphasia often use neologisms, and may perseverate if they try to replace the words they
can't find with sounds.
Commonly, substitutions involve picking another (actual) word starting with the same sound (e.g. clocktower -
colander), picking another semantically related to the first (e.g. letter - scroll), or picking one phonetically similar
to the intended one (e.g. lane - late).
Causes
Aphasia usually results from lesions to the language-relevant areas of the frontal, temporal and parietal lobes
of the brain, such as Broca's area, Wernicke's area, and the neural pathways between them. These areas are
almost always located in the left hemisphere, and in most people this is where the ability to produce and
comprehend language is found. However, in a very small number of people, language ability is found in the
right hemisphere. In either case, damage to these language areas can be caused by a stroke, traumatic brain
injury, or otherbrain injury. Aphasia may also develop slowly, as in the case of a brain tumor or
progressive neurological disease, e.g., Alzheimer's orParkinson's disease. It may also be caused by a
sudden hemorrhagic event within the brain. Certain chronic neurological disorders, such
asepilepsy or migraine, can also include transient aphasia as a prodromal or episodic symptom. Aphasia is
also listed as a rare side effect of the fentanyl patch, an opioid used to control chronic pain.
Treatment
There is no one treatment proven to be effective for all types of aphasias. Melodic intonation therapy is often
used to treat non-fluent aphasia and has proved to be very effective in some cases.
Apraxia
Apraxia is a disorder caused by damage to specific areas of the cerebrum, characterized by loss of the ability
to execute or carry out learned purposeful movements, despite having the desire and the physical ability to
perform the movements. It is a disorder of motor planningwhich may be acquired or developmental, but may
not be caused by incoordination, sensory loss, or failure to comprehend simple commands (which can be
tested by asking the person to recognize the correct movement from a series). Apraxia should not be confused
with aphasia, an inability to produce and/or comprehend language; abulia, the lack of desire to carry out an
action; or allochiria, in which patients perceive stimuli to one side of the body as occurring on the other.
The root word of apraxia is praxis, Greek for an act, work, or deed. It is preceded by a privative a,
meaning without.
Types
There are several types of apraxia including:
 ideomotor (inability to carry out a motor command; for example, "act as if you are brushing your teeth"
or "salute") - the form most frequently encountered by physicians;
 limb apraxia when movements of the arms and legs are involved;
 nonverbal-oral or buccofacial (inability to carry out facial movements on command; e.g.,
lick lips, whistle, cough, or wink);
 ideational (inability to create a plan for or idea of a specific movement; for example, "pick up this pen
and write down your name");
 limb-kinetic (inability to make fine, precise movements with a limb);
 verbal (difficulty planning the movements necessary for speech), also known as Apraxia of Speech
(see below);
 constructional (inability to draw or construct simple configurations), such as intersecting pentagons;
 oculomotor (difficulty moving the eye, especially with saccade movements).
 gait apraxia
Each type may be tested at decreasing levels of complexity; if the person tested fails to execute the
commands, you can make the movement yourself and ask that the person mimic it, or you can even give them
a real object (like a toothbrush) and ask them to use it.
Apraxia may be accompanied by a language disorder called aphasia.
Apraxia of speech
Symptoms of Acquired Apraxia of speech (AOS) and Childhood Apraxia of Speech (CAS) include inconsistent
articulatory errors, groping oral movements to locate the correct articulatory position, and increasing errors with
increasing word and phrase length. AOS often co-occurs with Oral Apraxia (during both speech and non-
speech movements) and Limb Apraxia.
Childhood Apraxia of Speech (CAS) presents in children who have no evidence of difficulty with strength or
range of motion of the articulators, but are unable to execute speech movements because of motor planning
and coordination problems. This is not to be confused with phonological impairments in children with normal
coordination of the articulators during speech.
Acquired apraxia of speech involves the loss of previously acquired speech levels. It occurs in both children
and adults who have (prior to the onset of apraxia) acquired some level of speaking ability. Unlike Childhood
Apraxia of Speech, AOS is typically the result of a stroke, tumor, or other known neurological illness or injury.
Causes
Ideomotor apraxia is almost always caused by lesions in the language-dominant (usually left) hemisphere of
the brain; and, as such, these patients often have concomitant aphasia, especially of
the Broca or conduction type. Left-side ideomotor apraxia may be caused by a lesion of the anterior corpus
callosum.
Ideational apraxia is commonly associated with confusion states and dementia.
Constructional apraxia is associated with hepatic encephalopathy due to cerebral edema.
Treatment
Recommended treatment for individuals with apraxia includes physical therapy, occupational
therapy and/or speech therapy.
Prognosis
The prognosis for individuals with apraxia varies. With therapy, some patients improve significantly, while
others may show very little improvement. Some individuals with apraxia may benefit from the use of
a communication aid.
Alexia
Alexia is a type ofaphasia where damage to the brain causes a patient to lose the ability to read. It is also
called word blindness, text blindness or visual aphasia.
Those who suffer from "alexia" and "dyslexia" can have similar difficulties, however, "alexia" refers to an
acquired reading disability, where reading ability had previously been developed, usually occurring in adulthood
conditions, while "dyslexia" refers to developmental reading disability.
Classification
There are two groups of alexia.
 The first or main group is "the central dyslexia" group which includes surface dyslexia, semantic
dyslexia, phonological dyslexia, anddeep dyslexia.
 The second group, "the peripheral dyslexia" group, includes neglect dyslexia, attentional dyslexia,
and pure alexia which is also known as alexia without agraphia.
Causes
Alexia typically occurs following damage to the left hemisphere of the brain or to the areas of
the occipital and parietal lobes, which are responsible for processing auditory, phonological and visual aspects
of language. The region at the junction of occipital and temporal lobes (sometimes called the occipito-temporal
junction) coordinates information that is gathered from visual and auditory processing and assigns meaning to
the stimulus. Alexia can also occur following damage to the inferior frontal. Damage to these different areas of
the cortex result in somewhat different patterns of difficulty in affected individuals. In some cases, a stroke can
cause alexia.
Presentation
Alexia may be accompanied by expressive and/or receptive aphasia (the inability to produce or comprehend
spoken language). Alexia can also co-occur with agraphia, the specific loss of the ability to produce written
language even when other manual motor abilities are intact. In other cases, damage is restricted to areas
responsible for input processing. The result is known as pure alexia. In this scenario, an individual's ability to
produce written language is spared even though they are unable to understand written text.
Alexia without agraphia results from a left occipital splenium of the corpus callosum lesion.
Dementia
Dementia (taken from Latin, originally meaning "madness", from de- "without" + ment, the root of mens "mind")
is a serious loss of cognitive ability in a previously unimpaired person, beyond what might be expected from
normal aging. It may be static, the result of a unique global brain injury, or progressive, resulting in long-term
decline due to damage or disease in the body. Although dementia is far more common in
the geriatric population, it may occur in any stage of adulthood.
The overwhelming factor emerging from genetic studies of the dementias and other central nervous system
neurodegenerative conditions is abnormalities of protein handling.
This age cutoff is defining, as similar sets of symptoms due to organic brain syndrome or dysfunction, are given
different names in populations younger than adult. Up to the end of the nineteenth century, dementia was a
much broader clinical concept. Well into the second half of the twentieth century, dementia of the elderly was
called senile dementia or senilityand viewed as a normal aspect of growing old rather than as being caused
by any specific diseases, while Alzheimer's disease was seen as a rare disease of middle age, until the
neurologist Robert Katzmann signaled a link between "senile dementia" and Alzheimer's.
Dementia is a non-specific illness syndrome (set of signs and symptoms) in which affected areas of cognition
may be memory, attention,language, and problem solving. It is normally required to be present for at least 6
months to be diagnosed; cognitive dysfunction that has been seen only over shorter times, in particular less
than weeks, must be termed delirium. In all types of general cognitive dysfunction, higher mental functions are
affected first in the process.
Especially in the later stages of the condition, affected persons may be disoriented in time (not knowing what
day of the week, day of the month, or even what year it is), in place (not knowing where they are), and in
person (not knowing who they are or others around them). Dementia, though often treatable to some degree, is
usually due to causes that are progressive and incurable.
Symptoms of dementia can be classified as either reversible or irreversible, depending upon the etiology of the
disease. Less than 10% of cases of dementia are due to causes that may presently be reversed with treatment.
Causes include many different specific disease processes, in the same way that symptoms of organ
dysfunction such as shortness of breath, jaundice, or pain are attributable to many etiologies.
Without careful assessment of history, the short-term syndrome of delirium (often lasting days to weeks) can
easily be confused with dementia, because they have all symptoms in common, save duration. Some mental
illnesses, including depression and psychosis, may also produce symptoms that must be differentiated from
both delirium and dementia.
Chronic use of substances such as alcohol can also predispose the patient to cognitive changes suggestive of
dementia, although moderate intake may have a protective effect.
Signs and symptoms
Comorbidities
Dementia is not merely a problem of memory. It reduces the ability to learn, reason, retain or recall past
experience and there is also loss of patterns of thoughts, feelings and activities (Gelder et al 2005). Additional
mental and behavioral problems often affect people who have dementia, and may influence quality of life,
caregivers, and the need for [Link] dementia worsens individuals may neglect themselves and
may become disinhibited,the individual may become incontinent as their condition worsens (Gelder et al 2005).
Depression affects 20–30% of people who have dementia, and about 20% have anxiety. Psychosis (often
delusions of persecution) and agitation/aggression also often accompany dementia. Each of these needs to be
assessed and treated independent of the underlying dementia.
Risk to self and others
The Canadian Medical Association Journal has reported that driving with dementia could lead to severe injury
or even death to self and others. Doctors should advise appropriate testing on when to quit driving.
In the United States, Florida's Baker Act allows law enforcement and the judiciary to force mental evaluation for
those suspected of suffering from dementia or other mental incapacities.
In the United Kingdom, as with all mental disorders, where a sufferer could potentially be a danger to
themselves or others, they can be detained under the Mental Health Act 1983 for the purposes of assessment,
care and treatment. This is a last resort, and usually avoided if the patient has family or friends who can ensure
care.
The United Kingdom DVLA (Driving & Vehicle Licensing Agency) states that dementia sufferers who
specifically suffer with poor short term memory, disorientation, lack of insight or judgment are almost certainly
not fit to drive—and in these instances, the DVLA must be informed so said license can be revoked. They do
however acknowledge low-severity cases and early sufferers, and those drivers may be permitted to drive
pending medical report.
Causes
Fixed cognitive impairment
Various types of brain injury, occurring as a single event, may cause irreversible but fixed cognitive
impairment. Traumatic brain injury may cause generalized damage to the white matter of the brain (diffuse
axonal injury), or more localized damage (as also may neurosurgery). A temporary reduction in the brain's
supply of blood or oxygen may lead to hypoxic-ischemic injury. Strokes (ischemic stroke, or intracerebral,
subarachnoid, subdural or extradural hemorrhage) or infections (meningitis and/or encephalitis) affecting the
brain, prolonged epilepticseizures and acute hydrocephalus may also have long-term effects on cognition.
Excessive alcohol use may cause alcohol dementia,Wernicke's encephalopathy and/or Korsakoff's psychosis,
and certain other recreational drugs may cause substance-induced persisting dementia; once overuse ceases,
the cognitive impairment is persistent but not progressive.
Slowly progressive dementia
Dementia which begins gradually and worsens progressively over several years is usually caused
by neurodegenerative disease; that is, by conditions affecting only or primarily the neurons of the brain and
causing gradual but irreversible loss of function of these cells. Less commonly, a non-degenerative condition
may have secondary effects on brain cells, which may or may not be reversible if the condition is treated.
The causes of dementia depend on the age at which symptoms begin. In the elderly population (usually
defined in this context as over 65 years of age), a large majority of cases of dementia are caused
by Alzheimer's disease, vascular dementia or both. Dementia with Lewy bodies is another fairly common
cause, which again may occur alongside either or both of the other causes. Hypothyroidismsometimes causes
slowly progressive cognitive impairment as the main symptom, and this may be fully reversible with
treatment. Normal pressure hydrocephalus, though relatively rare, is important to recognize since treatment
may prevent progression and improve other symptoms of the condition. However, significant cognitive
improvement is unusual.
Dementia is much less common under 65 years of age. Alzheimer's disease is still the most frequent cause,
but inherited forms of the disease account for a higher proportion of cases in this age group. Frontotemporal
lobar degeneration and Huntington's disease account for most of the remaining cases. Vascular dementia also
occurs, but this in turn may be due to underlying conditions (includingantiphospholipid
syndrome, CADASIL, MELAS, homocystinuria, moyamoya and Binswanger's disease). People who receive
frequent head trauma, such as boxers or some martial artists, are at risk of dementia pugilistica.
In young adults (up to 40 years of age) who were previously of normal intelligence, it is very rare to develop
dementia without other features of neurological disease, or without features of disease elsewhere in the body.
Most cases of progressive cognitive disturbance in this age group are caused by psychiatric illness, alcohol or
other drugs, or metabolic disturbance. However, certain genetic disorders can cause true neurodegenerative
dementia at this age. These include familial Alzheimer's
disease, SCA17 (dominant inheritance); adrenoleukodystrophy (X-linked); Gaucher's disease type
3, metachromatic leukodystrophy, Niemann-Pick disease type C, pantothenate kinase-associated
neurodegeneration, Tay-Sachs disease and Wilson's disease (all recessive). Wilson's disease is particularly
important since cognition can improve with treatment.
At all ages, a substantial proportion of patients who complain of memory difficulty or other cognitive symptoms
are suffering from depressionrather than a neurodegenerative disease. Vitamin deficiencies and chronic
infections may also occur at any age; they usually cause other symptoms before dementia occurs, but
occasionally mimic degenerative dementia. These include deficiencies of vitamin B12, folate or niacin, and
infective causes including cryptococcal meningitis, HIV, Lyme disease, progressive multifocal
leukoencephalopathy, subacute sclerosing panencephalitis, syphilis and Whipple's disease.
Rapidly progressive dementia
Creutzfeldt-Jakob disease typically causes a dementia which worsens over weeks to months, being caused
by prions. The common causes of slowly progressive dementia also sometimes present with rapid
progression: Alzheimer's disease, dementia with Lewy bodies,frontotemporal lobar
degeneration (including corticobasal degeneration and progressive supranuclear palsy).
On the other hand, encephalopathy or delirium may develop relatively slowly and resemble dementia. Possible
causes include brain infection (viral encephalitis, subacute sclerosing panencephalitis, Whipple's disease) or
inflammation (limbic encephalitis, Hashimoto's encephalopathy, cerebral vasculitis); tumors such
as lymphoma or glioma; drug toxicity (e.g. anticonvulsant drugs); metabolic causes such as liver
failure or kidney failure; and chronic subdural hematoma.
Dementia as a feature of other conditions
There are many other medical and neurological conditions in which dementia only occurs late in the illness, or
as a minor feature. For example, a proportion of patients with Parkinson's disease develop dementia, though
widely varying figures are quoted for this proportion. When dementia occurs in Parkinson's disease, the
underlying cause may be dementia with Lewy bodies orAlzheimer's disease, or both. Cognitive impairment also
occurs in the Parkinson-plus syndromes of progressive supranuclear palsy andcorticobasal degeneration (and
the same underlying pathology may cause the clinical syndromes of frontotemporal lobar degeneration).
Chronic inflammatory conditions of the brain may affect cognition in the long term, including Behçet's
disease, multiple sclerosis,sarcoidosis, Sjögren's syndrome and systemic lupus erythematosus. Although the
acute porphyrias may cause episodes of confusion and psychiatric disturbance, dementia is a rare feature of
these rare diseases.
Aside from those mentioned above, inherited conditions which may cause dementia alongside other features
include:
 Alexander disease
 Canavan disease
 Cerebrotendinous xanthomatosis
 DRPLA
 Fragile X-associated tremor/ataxia syndrome
 Glutaric aciduria type 1
 Krabbe's disease
 Maple syrup urine disease
 Niemann Pick disease type C
 Kufs' disease
 Neuroacanthocytosis
 Organic acidemias
 Pelizaeus-Merzbacher disease
 Urea cycle disorders
 Sanfilippo syndrome type B
 Spinocerebellar ataxia type 2
Diagnosis
Proper differential diagnosis between the types of dementia (cortical and subcortical) will require, at the least,
referral to a specialist, e.g., a geriatric internist, geriatric psychiatrist, neurologist, neuropsychologist or
geropsychologist. Duration of symptoms
must evident for at least six months for a
diagnosis of dementia or organic brain Sensitivity and specificity of common tests for
syndrome to be made (ICD-10). dementia
Cognitive testing Test Sensitivity Specificity Reference
There exist some brief tests (5–15
minutes) that have reasonable reliability MMSE 71%-92% 56%-96%
and can be used in the office or other
setting to screen cognitive status. 3MS 83%-93.5% 85%-90%
Examples of such tests include AMTS 73%-100% 71%-100%
theabbreviated mental test score (AMTS),
the mini mental state
examination (MMSE), Modified Mini-Mental State Examination (3MS), the Cognitive Abilities Screening
Instrument (CASI), and the clock drawing test. Scores must be interpreted in the context of the person's
educational and other background, and the particular circumstances; for example, a person highly depressed
or in great pain will not be expected to do well on many tests of mental ability.
While many tests have been studied, and some may emerge as better alternatives to the MMSE, presently the
MMSE is the best studied and most commonly used.
Another approach to screening for dementia is to ask an informant (relative or other supporter) to fill out a
questionnaire about the person's everyday cognitive functioning. Informant questionnaires provide
complementary information to brief cognitive tests. Probably the best known questionnaire of this sort is
the Informant Questionnaire on Cognitive Decline in the Elderly (IQCODE). On the other hand the General
Practitioner Assessment Of Cognition combines both, a patient assessment and an informant interview. It was
specifically designed for the use in the primary care setting and is also available as a web-based test. It can be
accessed at [Link].
Further evaluation includes retesting at another date, and administration of other tests of mental function.
Laboratory tests
Routine blood tests are also usually performed to rule out treatable causes. These tests include vitamin
B12, folic acid, thyroid-stimulating hormone (TSH), C-reactive protein, full blood
count, electrolytes, calcium, renal function, and liver enzymes. Abnormalities may suggestvitamin
deficiency, infection or other problems that commonly cause confusion or disorientation in the elderly. The
problem is complicated by the fact that these cause confusion more often in persons who have early dementia,
so that "reversal" of such problems may ultimately only be temporary.
Testing for alcohol and other known dementia-inducing drugs may be indicated.
Imaging
A CT scan or magnetic resonance imaging (MRI scan) is commonly performed, although these modalities do
not have optimal sensitivity for the diffuse metabolic changes associated with dementia in a patient that shows
no gross neurological problems (such as paralysis or weakness) on neurological exam. CT or MRI may
suggest normal pressure hydrocephalus, a potentially reversible cause of dementia, and can yield information
relevant to other types of dementia, such as infarction (stroke) that would point at a vascular type of dementia.
The functional neuroimaging modalities of SPECT and PET are more useful in assessing long-standing
cognitive dysfunction, since they have shown similar ability to diagnose dementia as a clinical exam. The ability
of SPECT to differentiate the vascular cause from the Alzheimer's disease cause of dementias, appears to be
superior to differentiation by clinical exam.
Recent research has established the value of PET imaging using carbon-11 Pittsburgh Compound B as a
radiotracer (PIB-PET) in predictive diagnosis of various kinds of dementia, in particular Alzheimer's disease.
Studies from Australia have found PIB-PET to be 86% accurate in predicting which patients with mild cognitive
impairment would develop Alzheimer's disease within two years. In another study, carried out using 66 patients
seen at the University of Michigan, PET studies using either PIB or another radiotracer, carbon-11
dihydrotetrabenazine (DTBZ), led to more accurate diagnosis for more than one-fourth of patients with mild
cognitive impairment or mild dementia.
Prevention
It appears that the regular moderate consumption of alcohol (beer, wine, or distilled spirits) and
a Mediterranean diet may reduce risk. A study has shown a link between high blood pressure and developing
dementia. The study, published in the Lancet Neurology journal July 2008, found that blood pressure lowering
medication reduced dementia by 13%.
Brain-derived neurotrophic factor (BDNF) expression is associated with some dementia types.
A Canadian study found that a lifetime of bilingualism delays the onset of dementia by an average of four years
when compared tomonolingual patients.
Management
Except for the treatable types listed above, there is no cure to this illness. Cholinesterase inhibitors are often
used early in the disease course. Cognitive and behavioral interventions may also be appropriate. Educating
and providing emotional support to the caregiver (or carer) is of importance as well (see also elderly care).
Pain and dementia
As they age, people experience more health problems, and most health problems associated with aging carry a
substantial burden of pain; so, between 25% and 50% of older adults experience persistent pain. Seniors with
dementia experience the same prevalence of conditions likely to cause pain as seniors without dementia. Pain
is often overlooked in older adults and, when screened for, often poorly assessed, especially among those with
dementia. Beyond the issue of humane care, unrelieved pain has functional implications. Persistent pain can
lead to decreased ambulation, depressed mood, sleep disturbances, impaired appetite and exacerbation of
cognitive impairment, and pain-related interference with activity is a factor contributing to falls in the elderly.
Although persistent pain in the person with dementia is difficult to communicate, diagnose and treat, failure to
address persistent pain has profound functional, psychosocial and quality of life implications for this vulnerable
population. Health professionals often lack the skills and usually lack the time needed to recognize, accurately
assess and adequately monitor pain in people with dementia. Family members and friends can make a
valuable contribution to the care of a person with dementia by learning to recognize and assess their pain.
Educational resources (such as the Understand Pain and Dementia tutorial) and observational assessment
tools are available.
Medications
 Acetylcholinesterase inhibitors: Tacrine (Cognex), donepezil (Aricept), galantamine (Razadyne),
and rivastigmine (Exelon) are approved by the United States Food and Drug Administration (FDA) for
treatment of dementia induced by Alzheimer's disease. They may be useful for other similar diseases
causing dementia such as Parkinsons or vascular dementia.
 N-methyl-D-aspartate Blockers. Memantine (Namenda) is a drug representative of this class. It can be
used in combination with acetylcholinesterase inhibitors.
Off label
 Amyloid deposit inhibitors: Minocycline and Clioquinoline, antibiotics, may help
reduce amyloid deposits in the brains of persons with Alzheimer's disease.
 Antidepressant drugs: Depression is frequently associated with dementia and generally worsens the
degree of cognitive and behavioralimpairment. Antidepressants effectively treat the cognitive and
behavioral symptoms of depression in patients with Alzheimer's disease, but evidence for their use in other
forms of dementia is weak.
 Anxiolytic drugs: Many patients with dementia experience anxiety symptoms.
Although benzodiazepines like diazepam (Valium) have been used for treating anxiety in other situations,
they are often avoided because they may increase agitation in persons with dementia and are likely to
worsen cognitive problems or are too sedating. Buspirone (Buspar) is often initially tried for mild-to-
moderate anxiety. There is little evidence for the effectiveness of benzodiazepines in dementia, whereas
there is evidence for the effectivess of antipsychotics (at low doses).
 Selegiline, a drug used primarily in the treatment of Parkinson's disease, appears to slow the
development of dementia. Selegiline is thought to act as an antioxidant, preventing free radical damage.
However, it also acts as a stimulant, making it difficult to determine whether the delay in onset of dementia
symptoms is due to protection from free radicals or to the general elevation of brain activity from the
stimulant effect.
 Antipsychotic drugs: Both typical antipsychotics (such as Haloperidol) and atypical antipsychotics such
as (risperidone) increase the risk of death in dementia-associated psychosis. This means that any use of
antipsychotic medication for dementia-associated psychosis is off-label and should only be considered
after discussing the risks and benefits of treatment with these drugs, and after other treatment modalities
have failed. In the UK around 144,000 dementia sufferers are unnecessarily prescribed antipsychotic
drugs, around 2000 patients die as a result of taking the drugs each year.
Services
Adult daycare centers as well as special care units in nursing homes often provide specialized care for
dementia patients. Adult daycare centers offer supervision, recreation, meals, and limited health care to
participants, as well as providing respite for caregivers.
While some preliminary studies have found that music therapy may be useful in helping patients with dementia,
their quality has been low and no reliable conclusions can be drawn from them.
Epidemiology

Disability-adjusted life year for Alzheimer and other dementias per 100,000 inhabitants in 2002.
no data ≤ 50 50-70 70-90 90-110 110-130 130-150 150-170 170-190 190-210 210-230 230-250 ≥ 250
In a study issued by European researchers, it is estimated that about 35 million people have dementia
worldwide. They said that figure is likely to double every 20 years, to nearly 66 million in 2030 and 115 million
in 2050.
Alzheimer's disease

Alzheimer's disease (AD)—also called Alzheimer disease, senile dementia of the Alzheimer
type (SDAT), primary degenerative dementia of the Alzheimer's type(PDDAT), or Alzheimer's—is the
most common form of dementia. This incurable, degenerative, and terminal disease was first described by
German psychiatrist and neuropathologist Alois Alzheimer in 1906 and was named after him. Most often, it is
diagnosed in people over 65 years of age, although the less-prevalent early-onset Alzheimer's can occur much
earlier. In 2006, there were 26.6 million sufferers worldwide. Alzheimer's is predicted to affect 1 in 85 people
globally by 2050.
Although the course of Alzheimer's disease is unique for every individual, there are many common
symptoms. The earliest observable symptoms are often mistakenly thought to be 'age-related' concerns, or
manifestations of stress. In the early stages, the most commonly recognised symptom is inability to acquire
new memories, such as difficulty in recalling recently observed facts. When AD is suspected, the diagnosis is
usually confirmed with behavioural assessments and cognitive tests, often followed by a brain scan if available.
As the disease advances, symptoms include confusion, irritability and aggression, mood swings, language
breakdown, long-term memory loss, and the general withdrawal of the sufferer as their senses
decline. Gradually, bodily functions are lost, ultimately leading to [Link] prognosis is difficult to
assess, as the duration of the disease varies. AD develops for an indeterminate period of time before becoming
fully apparent, and it can progress undiagnosed for years. The mean life expectancy following diagnosis is
approximately seven years. Fewer than three percent of individuals live more than fourteen years after
diagnosis.
The cause and progression of Alzheimer's disease are not well understood. Research indicates that the
disease is associated with plaquesand tangles in the brain. Currently used treatments offer a small
symptomatic benefit; no treatments to delay or halt the progression of the disease are as yet available. As of
2008, more than 500 clinical trials have been conducted for identification of a possible treatment for AD, but it
is unknown if any of the tested intervention strategies will show promising results. A number of non-invasive,
life-style habits have been suggested for the prevention of Alzheimer's disease, but there is a lack of adequate
evidence for a link between these recommendations and reduced degeneration. Mental stimulation, exercise,
and a balanced diet are suggested, as both a possible prevention and a sensible way of managing the disease.
Because AD cannot be cured and is degenerative, management of patients is essential. The role of the
main caregiver is often taken by the spouse or a close relative. Alzheimer's disease is known for placing a
great burden on caregivers; the pressures can be wide-ranging, involving social, psychological, physical, and
economic elements of the caregiver's life. In developed countries, AD is one of the most costly diseases to
society.
Characteristics
The disease course is divided into four stages, with progressive patterns
of cognitive and functional impairments.
Pre-dementia
The first symptoms are often mistaken as related to aging or stress. Detailed neuropsychological testing can
reveal mild cognitive difficulties up to eight years before a person fulfills the clinical criteria for diagnosis of
AD. These early symptoms can affect the most complex daily living activities. The most noticeable deficit is
memory loss, which shows up as difficulty in remembering recently learned facts and inability to acquire new
information.
Subtle problems with the executive functions of attentiveness, planning, flexibility, and abstract thinking, or
impairments in semantic memory(memory of meanings, and concept relationships), can also be symptomatic
of the early stages of AD. Apathy can be observed at this stage, and remains the most
persistent neuropsychiatric symptom throughout the course of the disease. The preclinical stage of the disease
has also been termed mild cognitive impairment, but whether this term corresponds to a different diagnostic
stage or identifies the first step of AD is a matter of dispute.
Early
In people with AD the increasing impairment of learning and memory eventually leads to a definitive diagnosis.
In a small portion of them, difficulties with language, executive functions, perception (agnosia), or execution of
movements (apraxia) are more prominent than memory problems. AD does not affect all memory capacities
equally. Older memories of the person's life (episodic memory), facts learned (semantic memory), and implicit
memory (the memory of the body on how to do things, such as using a fork to eat) are affected to a lesser
degree than new facts or memories.
Language problems are mainly characterised by a shrinking vocabulary and decreased word fluency, which
lead to a general impoverishment of oral and written language. In this stage, the person with Alzheimer's is
usually capable of adequately communicating basic ideas. While performing fine motor tasks such as writing,
drawing or dressing, certain movement coordination and planning difficulties (apraxia) may be present but they
are commonly unnoticed. As the disease progresses, people with AD can often continue to perform many tasks
independently, but may need assistance or supervision with the most cognitively demanding activities.
Moderate
Progressive deterioration eventually hinders independence; with subjects being unable to perform most
common activities of daily [Link] difficulties become evident due to an inability to recall vocabulary,
which leads to frequent incorrect word substitutions (paraphasias). Reading and writing skills are also
progressively lost. Complex motor sequences become less coordinated as time passes and AD progresses, so
the risk of falling increases. During this phase, memory problems worsen, and the person may fail to recognise
close relatives. Long-term memory, which was previously intact, becomes impaired.
Behavioural and neuropsychiatric changes become more prevalent. Common manifestations
are wandering, irritability and labile affect, leading to crying, outbursts of unpremeditated aggression, or
resistance to caregiving. Sundowning can also appear. Approximately 30% of patients develop illusionary
misidentifications and other delusional symptoms. Subjects also lose insight of their disease process and
limitations (anosognosia). Urinary incontinence can develop. These symptoms create stress for relatives and
caretakers, which can be reduced by moving the person from home care to other long-term care facilities.
Advanced
During this last stage of AD, the patient is completely dependent upon caregivers. Language is reduced to
simple phrases or even single words, eventually leading to complete loss of speech. Despite the loss of verbal
language abilities, patients can often understand and return emotional signals. Although aggressiveness can
still be present, extreme apathy and exhaustion are much more common results. Patients will ultimately not be
able to perform even the most simple tasks without assistance. Muscle mass and mobility deteriorate to the
point where they are bedridden, and they lose the ability to feed themselves. AD is a terminal illness with the
cause of death typically being an external factor such as infection of pressure ulcers or pneumonia, not the
disease itself.
Causes

Microscopy image of a neurofibrillary tangle, conformed by hyperphosphorylatedtau protein

Several competing hypotheses exist trying to explain the cause of the disease. The oldest, on which most
currently available drug therapies are based, is the cholinergic hypothesis, which proposes that AD is caused
by reduced synthesis of the neurotransmitter acetylcholine. The cholinergic hypothesis has not maintained
widespread support, largely because medications intended to treat acetylcholine deficiency have not been very
effective. Other cholinergic effects have also been proposed, for example, initiation of large-scale aggregation
of amyloid, leading to generalised neuroinflammation.
In 1991, the amyloid hypothesis postulated that amyloid beta (Aβ) deposits are the fundamental cause of the
disease. Support for this postulate comes from the location of the gene for theamyloid beta precursor
protein (APP) on chromosome 21, together with the fact that people withtrisomy 21 (Down Syndrome) who
have an extra gene copy almost universally exhibit AD by 40 years of age. Also APOE4, the major genetic risk
factor for AD, leads to excess amyloid buildup in the brain before AD symptoms arise. Thus, Aβ deposition
precedes clinical [Link] evidence comes from the finding that transgenic mice that express a mutant form
of the human APP gene develop fibrillar amyloid plaques and Alzheimer's-like brain pathology with spatial
learning deficits.
An experimental vaccine was found to clear the amyloid plaques in early human trials, but it did not have any
significant effect on dementia. Researchers have been led to suspect non-plaque Aβ oligomers (aggregates of
many monomers) as the primary pathogenic form of Aβ. These toxic oligomers, also referred to as amyloid-
derived diffusible ligands (ADDLs), bind to a surface receptor on neurons and change the structure of the
synapse, thereby disrupting neuronal communication. One receptor for Aβ oligomers may be the prion protein,
the same protein that has been linked to mad cow disease and the related human condition,Creutzfeldt-Jakob
disease, thus potentially linking the underlying mechanism of these neurodegenerative disorders with that of
Alzheimer's disease.
In 2009, this theory was updated, suggesting that a close relative of the beta-amyloid protein, and not
necessarily the beta-amyloid itself, may be a major culprit in the disease. The theory holds that an amyloid-
related mechanism that prunes neuronal connections in the brain in the fast-growth phase of early life may be
triggered by aging-related processes in later life to cause the neuronal withering of Alzheimer's disease. N-
APP, a fragment of APP from the peptide's N-terminus, is adjacent to beta-amyloid and is cleaved from APP by
one of the same enzymes. N-APP triggers the self-destruct pathway by binding to a neuronal receptor called
death receptor 6 (DR6, also known asTNFRSF21). DR6 is highly expressed in the human brain regions most
affected by Alzheimer's, so it is possible that the N-APP/DR6 pathway might be hijacked in the aging brain to
cause damage. In this model, beta-amyloid plays a complementary role, by depressing synaptic function.
A 2004 study found that deposition of amyloid plaques does not correlate well with neuron loss. This
observation supports the tau hypothesis, the idea that tau protein abnormalities initiate the disease cascade. In
this model, hyperphosphorylated tau begins to pair with other threads of tau. Eventually, they
form neurofibrillary tangles inside nerve cell bodies. When this occurs, the microtubules disintegrate, collapsing
the neuron's transport system. This may result first in malfunctions in biochemical communication between
neurons and later in the death of the cells. Herpes simplex virus type 1 has also been proposed to play a
causative role in people carrying the susceptible versions of the apoE gene.
Another hypothesis asserts that the disease may be caused by age-related myelin breakdown in the brain.
Demyelination leads to axonal transport disruptions, leading to loss of neurons that become stale. Iron released
during myelin breakdown is hypothesized to cause further damage. Homeostatic myelin repair processes
contribute to the development of proteinaceous deposits such as amyloid-beta and tau.
Oxidative stress is a significant cause in the formation of the pathology.
AD individuals show 70% loss of locus coeruleus cells that provide norepinephrine (in addition to its
neurotransmitter role) that locally diffuses from "varicosities" as an endogenous antiinflammatory agent in the
microenvironment around the neurons, glial cells, and blood vessels in the neocortex and hippocampus. It has
been shown that norepinephrine stimulates mouse microglia to suppress Aβ-induced production of cytokines
and their phagocytosis of Aβ. This suggests that degeneration of the locus ceruleus might be responsible for
increased Aβ deposition in AD brains.
Pathophysiology

Histopathologic image of senile plaques seen in the cerebral cortex of a person with Alzheimer's disease of presenile onset.
Silver impregnation.
Neuropathology
Alzheimer's disease is characterised by loss of neurons and synapses in the cerebral cortex and certain
subcortical regions. This loss results in gross atrophy of the affected regions, including degeneration in
the temporal lobe and parietal lobe, and parts of the frontal cortex and cingulate gyrus. Studies
using MRI and PET have documented reductions in the size of specific brain regions in patients as they
progressed from mild cognitive impairment to Alzheimer's disease, and in comparison with similar images from
healthy older adults.
Both amyloid plaques and neurofibrillary tangles are clearly visible by microscopy in brains of those afflicted by
AD. Plaques are dense, mostly insoluble deposits of amyloid-beta peptideand cellular material outside and
around neurons. Tangles (neurofibrillary tangles) are aggregates of the microtubule-associated protein tau
which has become hyperphosphorylated and accumulate inside the cells themselves. Although many older
individuals develop some plaques and tangles as a consequence of aging, the brains of AD patients have a
greater number of them in specific brain regions such as the temporal lobe. Lewy bodies are not rare in AD
patient's brains.
Biochemistry
Enzymes act on the APP (amyloid precursor protein) and cut it into fragments. The beta-amyloid fragment is crucial in the
formation of senile plaques in AD.
Alzheimer's disease has been identified as a protein misfolding disease (proteopathy), caused by accumulation
of abnormally folded A-beta and tau proteins in the brain. Plaques are made up of small peptides, 39–43 amino
acids in length, called beta-amyloid (also written as A-beta or Aβ). Beta-amyloid is a fragment from a larger
protein called amyloid precursor protein (APP), atransmembrane protein that penetrates through the neuron's
membrane. APP is critical to neuron growth, survival and post-injury repair. In Alzheimer's disease, an
unknown process causes APP to be divided into smaller fragments by enzymes through proteolysis. One of
these fragments gives rise to fibrils of beta-amyloid, which form clumps that deposit outside neurons in dense
formations known as senile plaques.

In Alzheimer's disease, changes in tau protein lead to the disintegration of microtubules in brain cells.
AD is also considered a tauopathy due to abnormal aggregation of the tau protein. Every neuron has
a cytoskeleton, an internal support structure partly made up of structures called microtubules. These
microtubules act like tracks, guiding nutrients and molecules from the body of the cell to the ends of
the axon and back. A protein called tau stabilizes the microtubules whenphosphorylated, and is therefore called
a microtubule-associated protein. In AD, tau undergoes chemical changes, becoming hyperphosphorylated; it
then begins to pair with other threads, creating neurofibrillary tangles and disintegrating the neuron's transport
system.
Disease mechanism
Exactly how disturbances of production and aggregation of the beta amyloid peptide gives rise to the pathology
of AD is not known. The amyloid hypothesis traditionally points to the accumulation of beta amyloid peptides as
the central event triggering neuron degeneration. Accumulation of aggregated amyloid fibrils, which are
believed to be the toxic form of the protein responsible for disrupting the cell's calciumion homeostasis,
induces programmed cell death (apoptosis). It is also known that Aβ selectively builds up in the mitochondria in
the cells of Alzheimer's-affected brains, and it also inhibits certain enzyme functions and the utilisation
of glucose by neurons.
Various inflammatory processes and cytokines may also have a role in the pathology of Alzheimer's
disease. Inflammation is a general marker of tissue damage in any disease, and may be either secondary to
tissue damage in AD or a marker of an immunological response.
Alterations in the distribution of different neurotrophic factors and in the expression of their receptors such as
the brain derived neurotrophic factor (BDNF) have been described in AD.
Genetics
The vast majority of cases of Alzheimer's disease are sporadic, meaning that they are not genetically inherited
although some genes may act as risk factors. On the other hand, around 0.1% of the cases are familial forms
of autosomal-dominant inheritance, which usually have an onset before age 65.
Most of autosomal dominant familial AD can be attributed to mutations in one of three genes: amyloid
precursor protein (APP) andpresenilins 1 and 2. Most mutations in the APP and presenilin genes increase the
production of a small protein called Aβ42, which is the main component of senile plaques. Some of the
mutations merely alter the size ratio between Aβ42 and the other major forms—e.g., Aβ40—without increasing
Aβ42 levels. This suggests that presenilin mutations can cause disease even if they lower the total amount of
Aβ produced and may point to other roles of presenilin or a role for alterations in the function of APP and/or its
fragments other than Aβ.
Most cases of Alzheimer's disease do not exhibit autosomal-dominant inheritance and are termed sporadic AD.
Nevertheless genetic differences may act as risk factors. The best known genetic risk factor is the inheritance
of the ε4 allele of the apolipoprotein E(APOE). Between 40 and 80% of patients with AD possess at least one
apoE4 allele. The APOE4 allele increases the risk of the disease by three times in heterozygotes and by 15
times in homozygotes. Geneticists agree that numerous other genes also act as risk factors or have protective
effects that influence the development of late onset Alzheimer's disease. Over 400 genes have been tested for
association with late-onset sporadic AD, most with null results.
Diagnosis
PET scan of the brain of a person with AD showing a loss of function in the temporal lobe
Alzheimer's disease is usually diagnosed clinically from the patient history, collateral history from relatives, and
clinical observations, based on the presence of characteristic neurological andneuropsychological features and
the absence of alternative conditions. Advanced medical imaging with computed tomography (CT) or magnetic
resonance imaging (MRI), and with single photon emission computed tomography (SPECT) or positron
emission tomography (PET) can be used to help exclude other cerebral pathology or subtypes of
dementia. Moreover, it may predict conversion from prodromal stages (mild cognitive impairment) to
Alzheimer's disease.
Assessment of intellectual functioning including memory testing can further characterise the state of the
disease. Medical organisations have created diagnostic criteria to ease and standardise the diagnostic process
for practicing physicians. The diagnosis can be confirmed with very high accuracy post-mortem when brain
material is available and can be examined histologically.[8
Criteria
The National Institute of Neurological and Communicative Disorders and Stroke (NINCDS) and theAlzheimer's
Disease and Related Disorders Association (ADRDA, now known as the Alzheimer's Association) established
the most commonly used NINCDS-ADRDA Alzheimer's Criteria for diagnosis in 1984,[8 extensively updated in
2007.[8 These criteria require that the presence of cognitive impairment, and a suspected dementia syndrome,
be confirmed by neuropsychological testing for a clinical diagnosis of possible or probable AD.
A histopathologicconfirmation including a microscopic examination of brain tissue is required for a definitive
diagnosis. Good statistical reliability and validityhave been shown between the diagnostic criteria and definitive
histopathological confirmation.[8 Eight cognitive domains are most commonly impaired in AD—
memory, language, perceptual skills, attention, constructive abilities, orientation, problem solving and functional
abilities. These domains are equivalent to the NINCDS-ADRDA Alzheimer's Criteria as listed in the Diagnostic
and Statistical Manual of Mental Disorders (DSM-IV-TR) published by the American Psychiatric Association.[8[8
Techniques

Neuropsychological screening tests can help in the diagnosis of AD. In them patients have to copy drawings similar to the
one shown in the picture, remember words, read, and subtract serial numbers.
Neuropsychological tests such as the mini-mental state examination (MMSE), are widely used to evaluate the
cognitive impairments needed for diagnosis. More comprehensive test arrays are necessary for high reliability
of results, particularly in the earliest stages of the disease. [8[8 Neurological examination in early AD will usually
provide normal results, except for obvious cognitive impairment, which may not differ from that resulting from
other diseases processes, including other causes of dementia.
Further neurological examinations are crucial in the differential diagnosis of AD and other [Link]
with family members are also utilised in the assessment of the disease. Caregivers can supply important
information on the daily living abilities, as well as on the decrease, over time, of the person's mental function. A
caregiver's viewpoint is particularly important, since a person with AD is commonly unaware of his own deficits.
[8
Many times, families also have difficulties in the detection of initial dementia symptoms and may not
communicate accurate information to a physician.[8
Another recent objective marker of the disease is the analysis of cerebrospinal fluid for amyloid beta or tau
proteins,[8 both total tau protein and phosphorylated tau 181P protein concentrations. Searching for these proteins
using a spinal tap can predict the onset of Alzheimer's with a sensitivity of between 94% and 100%. When used
in conjunction with existing neuroimaging techniques, doctors can identify patients with significant memory loss
who are already developing the [Link] fluid tests are commercially available, unlike the latest
neuroimaging technology. Alzheimer's was diagnosed in one-third of the people who did not have any
symptoms in a 2010 study, meaning that disease progression occurs well before symptoms occur.
Supplemental testing provides extra information on some features of the disease or is used to rule out other
diagnoses. Blood tests can identify other causes for dementia than AD—causes which may, in rare cases, be
reversible. It is common to perform thyroid function tests, assess B12, rule out syphillis, rule out metabolic
problems (including tests for kidney function, electrolyte levels and for diabetes), assess levels of heavy metals
(e.g. lead, mercury) and anemia. (See differential diagnosis for Dementia). (It is also necessary to rule
outdelirium).
Psychological tests for depression are employed, since depression can either be concurrent with AD, an early
sign of cognitive impairment, or even the cause.
Imaging
When available as a diagnostic tool, single photon emission computed tomography (SPECT) and positron
emission tomography (PET) neuroimaging are used to confirm a diagnosis of Alzheimer's in conjunction with
evaluations involving mental status examination. In a person already having dementia, SPECT appears to be
superior in differentiating Alzheimer's disease from other possible causes, compared with the usual attempts
employing mental testing and medical history analysis. Advances have led to the proposal of new diagnostic
criteria.[8
A new technique known as PiB PET has been developed for directly and clearly imaging beta-amyloid
deposits in vivo using a tracer thatbinds selectively to the A-beta deposits. The PiB-PET compound
uses carbon-11 PET scanning. Recent studies suggest that PiB-PET is 86% accurate in predicting which
people with mild cognitive impairment will develop Alzheimer's disease within two years, and 92% accurate in
ruling out the likelihood of developing Alzheimer's.0
A similar PET scanning radiopharmaceutical compound called (E)-4-(2-(6-(2-(2-(2-(8F]-
18
fluoroethoxy)ethoxy)ethoxy)pyridin-3-yl)vinyl)-N-methyl benzenamine, or F AV-45, or florbetapir-fluorine-18, or
simply florbetapir, contains the longer-lasting radionuclide fluorine-18, has recently been created, and tested as
a possible diagnostic tool in Alzheimer's patients.0000 Florbetapir, like PiB, binds to beta-amyloid, but due to its
use of fluorine-18 has a half-life of 110 minutes, in contrast to PiB's radioactive half life of 20 minutes. Wong et
[Link] that the longer life allowed the tracer to accumulate significantly more in the brains of the AD patients,
particularly in the regions known to be associated with beta-amyloid deposits.0
One review predicted that amyloid imaging is likely to be used in conjunction with other markers rather than as
an alternative.0
Volumetric MRI can detect changes in the size of brain regions. Measuring those regions that atrophy during
the progress of Alzheimer's disease is showing promise as a diagnostic indicator. It may prove less expensive
than other imaging methods currently under study.0
Recent studies suggest that brain metabolite levels may be utilized as biomarkers for Alzheimer's disease. 0
Prevention

Intellectual activities such as playingchess or regular social interaction have been linked to a reduced risk of AD in
epidemiological studies, although no causal relationship has been found.
At present, there is no definitive evidence to support that any particular measure is effective in preventing
AD.0 Global studies of measures to prevent or delay the onset of AD have often produced inconsistent results.
However, epidemiological studies have proposed relationships between certain modifiable factors, such as
diet, cardiovascular risk, pharmaceutical products, or intellectual activities among others, and a population's
likelihood of developing AD. Only further research, including clinical trials, will reveal whether these factors can
help to prevent AD.0
Although cardiovascular risk factors, such as hypercholesterolemia, hypertension, diabetes, and smoking, are
associated with a higher risk of onset and course of AD, 11 statins, which arecholesterol lowering drugs, have
not been effective in preventing or improving the course of the disease. 11 The components of a Mediterranean
diet, which include fruit and vegetables,bread, wheat and other cereals, olive oil, fish, and red wine, may all
individually or together reduce the risk and course of Alzheimer's disease. 1 Its beneficial cardiovascular effect
has been proposed as the mechanism of action. 1 There is limited evidence that light to moderate use of
alcohol, particularly red wine, is associated with lower risk of AD.1
Reviews on the use of vitamins have not found enough evidence of efficacy to recommend vitamin C, 1 E,11 or
folic acid with or without vitamin B 12,1 as preventive or treatment agents in AD. Additionally vitamin E is
associated with important health risks.1 Trials examining folic acid (B9) and other B vitamins failed to show any
significant association with cognitive decline.1 Docosahexaenoic acid, an Omega 3 fatty acid, has not been
found to slow decline.2
Long-term usage of non-steroidal anti-inflammatory drug (NSAIDs) is associated with a reduced likelihood of
developing AD.2 Humanpostmortem studies, in animal models, or in vitro investigations also support the notion
that NSAIDs can reduce inflammation related to amyloid plaques. 2 However trials investigating their use as
palliative treatment have failed to show positive results while no prevention trial has been
completed.2 Curcumin from the curry spice turmeric has shown some effectiveness in preventing brain
damage in mouse modelsdue to its anti-inflammatory properties.22 Hormone replacement therapy, although
previously used, is no longer thought to prevent dementia and in some cases may even be related to it. 22 There
is inconsistent and unconvincing evidence that ginkgo has any positive effect on cognitive impairment and
dementia,2 and a recent study concludes that it has no effect in reducing the rate of AD incidence. 2A 21-year
study found that coffee drinkers of 3–5 cups per day at midlife had a 65% reduction in risk of dementia in late-
life.2
People who engage in intellectual activities such as reading, playing board games, completing crossword
puzzles, playing musical instruments, or regular social interaction show a reduced risk for Alzheimer's
disease.2 This is compatible with the cognitive reservetheory, which states that some life experiences result in
more efficient neural functioning providing the individual a cognitive reserve that delays the onset of dementia
manifestations.2 Education delays the onset of AD syndrome, but is not related to earlier death after
diagnosis.3 Physical activity is also associated with a reduced risk of AD.3
Some studies have shown an increased risk of developing AD with environmental factors such the intake
of metals, particularlyaluminium,33 or exposure to solvents.3 The quality of some of these studies has been
criticised,3 and other studies have concluded that there is no relationship between these environmental factors
and the development of AD.3333
While some studies suggest that Extremely low frequency electromagnetic fields may increase the risk for
Alzheimer's disease, reviewers found that further epidemiological and laboratory investigations of this
hypothesis are needed.3 Smoking is a significant AD risk factor. 4Systemic markers of the innate immune
system are risk factors for late-onset AD.4
Management
There is no cure for Alzheimer's disease; available treatments offer relatively small symptomatic benefit but
remain palliative in nature. Current treatments can be divided into pharmaceutical, psychosocial and
caregiving.
Pharmaceutical

Three-dimensional molecular model ofdonepezil, an acetylcholinesterase inhibitorused in the treatment of AD symptoms

Molecular structure of memantine, a medication approved for advanced AD symptoms

Four medications are currently approved by regulatory agencies such as the U.S. Food and Drug
Administration (FDA) and the European Medicines Agency (EMA) to treat the cognitive manifestations of AD:
three are acetylcholinesterase inhibitors and the other is memantine, anNMDA receptor antagonist. No drug
has an indication for delaying or halting the progression of the disease.
Reduction in the activity of the cholinergic neurons is a well-known feature of Alzheimer's
disease.4 Acetylcholinesterase inhibitors are employed to reduce the rate at whichacetylcholine (ACh) is broken
down, thereby increasing the concentration of ACh in the brain and combating the loss of ACh caused by the
death of cholinergic neurons.4 As of 2008, the cholinesterase inhibitors approved for the management of AD
symptoms are donepezil (brand name Aricept),4 galantamine (Razadyne),4 and rivastigmine (branded
4 4
as Exelon andExelon Patch ). There is evidence for the efficacy of these medications in mild to moderate
Alzheimer's disease,44 and some evidence for their use in the advanced stage. Only donepezil is approved for
treatment of advanced AD dementia.5 The use of these drugs in mild cognitive impairment has not shown any
effect in a delay of the onset of AD. 5 The most common side effects are nausea and vomiting, both of which are
linked to cholinergic excess. These side effects arise in approximately 10–20% of users and are mild to
moderate in severity. Less common secondary effects include muscle cramps, decreased heart
rate (bradycardia), decreased appetite and weight, and increased gastric acid production.5
Glutamate is a useful excitatory neurotransmitter of the nervous system, although excessive amounts in
the brain can lead to cell death through a process called excitotoxicity which consists of the overstimulation of
glutamate receptors. Excitotoxicity occurs not only in Alzheimer's disease, but also in other neurological
diseases such as Parkinson's disease and multiple sclerosis.5 Memantine (brand
5
names Akatinol, Axura, Ebixa/Abixa, Memox and Namenda), is a noncompetitive NMDA receptor
antagonist first used as an anti-influenza agent. It acts on theglutamatergic system by blocking NMDA
receptors and inhibiting their overstimulation by glutamate.5 Memantine has been shown to be moderately
efficacious in the treatment of moderate to severe Alzheimer's disease. Its effects in the initial stages of AD are
unknown.5 Reported adverse events with memantine are infrequent and mild,
including hallucinations,confusion, dizziness, headache and fatigue.5 The combination of memantine and
donepezil has been shown to be "of statistically significant but clinically marginal effectiveness".5
Antipsychotic drugs are modestly useful in reducing aggression and psychosis in Alzheimer's patients with
behavioural problems, but are associated with serious adverse effects, such
as cerebrovascular events, movement difficulties or cognitive decline, that do not permit their routine
use.55 When used in the long-term, they have been shown to associate with increased mortality. 5
Medical marijuana appears to be effective in delaying Alzheimer's Disease. The active ingredient in
marijuana, THC, prevents the formation of deposits in the brain associated with Alzheimer's disease. THC was
found to inhibit acetylcholinesterase more effectively than commercially marketed drugs. THC was also found
to delay amylogenesis.66
Psychosocial intervention

A specifically designed room for sensory integration therapy, also called snoezelen; an emotion-oriented psychosocial
intervention for people with dementia
Psychosocial interventions are used as an adjunct to pharmaceutical treatment and can be classified within
behaviour-, emotion-, cognition- or stimulation-oriented approaches. Research on efficacy is unavailable and
rarely specific to AD, focusing instead on dementia in general.6
Behavioural interventions attempt to identify and reduce the antecedents and consequences of problem
behaviours. This approach has not shown success in improving overall functioning, 6but can help to reduce
some specific problem behaviours, such as incontinence.6 There is a lack of high quality data on the
effectiveness of these techniques in other behaviour problems such as wandering.66
Emotion-oriented interventions include reminiscence therapy, validation therapy,
supportivepsychotherapy, sensory integration, also called snoezelen, and simulated presence therapy.
Supportive psychotherapy has received little or no formal scientific study, but some clinicians find it useful in
helping mildly impaired patients adjust to their illness. 6 Reminiscence therapy (RT) involves the discussion of
past experiences individually or in group, many times with the aid of photographs, household items, music and
sound recordings, or other familiar items from the past. Although there are few quality studies on the
effectiveness of RT, it may be beneficial for cognitionand mood. 6 Simulated presence therapy (SPT) is based
on attachment theories and involves playing a recording with voices of the closest relatives of the person with
Alzheimer's disease. There is partial evidence indicating that SPT may reduce challenging behaviours.6 Finally,
validation therapy is based on acceptance of the reality and personal truth of another's experience, while
sensory integration is based on exercises aimed to stimulate senses. There is little evidence to support the
usefulness of these therapies.67
The aim of cognition-oriented treatments, which include reality orientation and cognitive retraining, is the
reduction of cognitive deficits. Reality orientation consists in the presentation of information about time, place or
person in order to ease the understanding of the person about its surroundings and his or her place in them.
On the other hand cognitive retraining tries to improve impaired capacities by exercitation of mental abilities.
Both have shown some efficacy improving cognitive capacities,77 although in some studies these effects were
transient and negative effects, such as frustration, have also been reported. 6
Stimulation-oriented treatments include art, music and pet therapies, exercise, and any other kind
of recreational activities. Stimulation has modest support for improving behaviour, mood, and, to a lesser
extent, function. Nevertheless, as important as these effects are, the main support for the use of stimulation
therapies is the change in the person's routine. 6
Caregiving
Since Alzheimer's has no cure and it gradually renders people incapable of tending for their own needs,
caregiving essentially is the treatment and must be carefully managed over the course of the disease.
During the early and moderate stages, modifications to the living environment and lifestyle can increase patient
safety and reduce caretaker burden.77 Examples of such modifications are the adherence to simplified routines,
the placing of safety locks, the labelling of household items to cue the person with the disease or the use of
modified daily life objects.677 The patient may also become incapable of feeding themselves, so they require
food in smaller pieces or pureed.7 When swallowing difficulties arise, the use of feeding tubes may be required.
In such cases, the medical efficacy and ethics of continuing feeding is an important consideration of the
caregivers and family members.77 The use of physical restraints is rarely indicated in any stage of the disease,
although there are situations when they are necessary to prevent harm to the person with AD or their
caregivers.6
As the disease progresses, different medical issues can appear, such as oral and dental disease, pressure
ulcers, malnutrition, hygieneproblems, or respiratory, skin, or eye infections. Careful management can prevent
them, while professional treatment is needed when they do arise. 88 During the final stages of the disease,
treatment is centred on relieving discomfort until death.8
A small recent study in the US concluded that patients whose caregivers had a realistic understanding of the
prognosis and clinical complications of late dementia were less likely to receive aggressive treatment near the
end of life. 8
Prognosis

Disability-adjusted life year for Alzheimer and other dementias per 100,000 inhabitants in 2004.
no data ≤ 50 50–70 70–90 90–110 110–130 130–150 150–170 170–190 190–210 210–230 230–250 ≥ 250
The early stages of Alzheimer's disease are difficult to diagnose. A definitive diagnosis is usually made once
cognitive impairment compromises daily living activities, although the person may still be living independently.
The symptoms will progress from mild cognitive problems, such as memory loss through increasing stages of
cognitive and non-cognitive disturbances, eliminating any possibility of independent living.
Life expectancy of the population with the disease is reduced.88 The mean life expectancy following diagnosis is
approximately seven years. Fewer than 3% of patients live more than fourteen years. Disease features
significantly associated with reduced survival are an increased severity of cognitive impairment, decreased
functional level, history of falls, and disturbances in the neurological examination. Other coincident diseases
such as heart problems, diabetes or history of alcohol abuse are also related with shortened survival.888 While
the earlier the age at onset the higher the total survival years, life expectancy is particularly reduced when
compared to the healthy population among those who are younger. 8 Men have a less favourable survival
prognosis than women.8
The disease is the underlying cause of death in 70% of all cases. Pneumonia and dehydrationare the most
frequent immediate causes of death, while cancer is a less frequent cause of death than in the general
population.8
 Epidemiology
Incidence rates Two main measures are used in epidemiological studies: incidence and
after age 658 prevalence. Incidence is the number of new cases per unit of person–time at risk
(usually number of new cases per thousand person–years); while prevalence is the
New affected total number of cases of the disease in the population at any given time.
Age per thousand Regarding incidence, cohort longitudinal studies (studies where a disease-free
person–years population is followed over the years) provide rates between 10 and 15 per
thousand person–years for all dementias and 5–8 for AD, 89 which means that half of
65–69 3 new dementia cases each year are AD. Advancing age is a primary risk factor for
70–74 6 the disease and incidence rates are not equal for all ages: every five years after the
age of 65, the risk of acquiring the disease approximately doubles, increasing from
75–79 9 3 to as much as 69 per thousand person years. 89 There are also sex differences in
80–84 23 the incidence rates, women having a higher risk of developing AD particularly in the
population older than 85.99
85–89 40 Prevalence of AD in populations is dependent upon different factors including
90– 69 incidence and survival. Since the incidence of AD increases with age, it is
particularly important to include the mean age of the population of interest. In the
United States, Alzheimer prevalence was estimated to be 1.6% in 2000 both overall
and in the 65–74 age group, with the rate increasing to 19% in the 75–84 group and to 42% in the greater than
84 group.9 Prevalence rates in less developed regions are lower. [dead link]9 The World Health
Organization estimated that in 2005, 0.379% of people worldwide had dementia, and that the prevalence would
increase to 0.441% in 2015 and to 0.556% in 2030. 9 Other studies have reached similar conclusions.9 Another
study estimated that in 2006, 0.40% of the world population (range 0.17–0.89%; absolute number 26.6 million,
range 11.4–59.4 million) were afflicted by AD, and that the prevalence rate would triple and the absolute
number would quadruple by 2050.
History

Alois Alzheimer's patient Auguste Deterin 1902. Hers was the first described case of what became known as Alzheimer's
disease.
The ancient Greek and Roman philosophers and physicians associated old age with increasingdementia. It
was not until 1901 that German psychiatrist Alois Alzheimer identified the first case of what became known as
Alzheimer's disease in a fifty-year-old woman he called Auguste D. Alzheimer followed her until she died in
1906, when he first reported the case publicly. 9 During the next five years, eleven similar cases were reported
in the medical literature, some of them already using the term Alzheimer's disease. The disease was first
described as a distinctive disease by Emil Kraepelin after suppressing some of the clinical (delusions and
hallucinations) and pathological features (arteriosclerotic changes) contained in the original report of Auguste
D.9 He included Alzheimer's disease, also named presenile dementia by Kraepelin, as a subtype of senile
dementia in the eighth edition of his Textbook of Psychiatry, published in 1910.9
For most of the 20th century, the diagnosis of Alzheimer's disease was reserved for individuals between the
ages of 45 and 65 who developed symptoms of dementia. The terminology changed after 1977 when a
conference on AD concluded that the clinical and pathological manifestations of presenile and senile dementia
were almost identical, although the authors also added that this did not rule out the possibility that they had
different causes.9 This eventually led to the diagnosis of Alzheimer's disease independently of age.9 The
term senile dementia of the Alzheimer type(SDAT) was used for a time to describe the condition in those over
65, with classical Alzheimer's disease being used for those younger. Eventually, the term Alzheimer's disease
was formally adopted in medical nomenclature to describe individuals of all ages with a characteristic common
symptom pattern, disease course, and neuropathology.0
Multi-infarct dementia
Multi-infarct dementia, also known as vascular dementia, is the second most common form
of dementia after Alzheimer's disease (AD) in older adults. The term refers to a group of syndromes caused by
different mechanisms all resulting in vascular lesions in the brain. Early detection and accurate diagnosis are
important, as vascular dementia is at least partially preventable.
The main subtypes of this disease are: mild cognitive impairment, multi-infarct dementia, vascular dementia
due to a strategic single infarct (affecting the thalamus, the anterior cerebral artery, the parietal lobes or
the cingulate gyrus), vascular dementia due to hemorrhagic lesions, small vessel disease (which includes
vascular dementia due to lacunar lesions and Binswanger's disease), and mixed Alzheimer's and vascular
dementia.
Vascular lesions can be the result of diffuse cerebrovascular disease or focal lesions (or a combination of both,
which is what is observed in the majority of cases). Mixed dementia is diagnosed when patients have evidence
of AD and cerebrovascular disease, either clinically or based on neuroimaging evidence of ischemic lesions. In
fact vascular dementia and Alzheimer's disease often coexist, especially in older patients with dementia.

arrows: lacunar infarcts

Epidemiology
Vascular dementia is the second most common cause of dementia in the United States and Europe in the
elderly, but it is the most common form in some parts of Asia. The prevalence of the illness is 1.5% in Western
countries and approximately 2.2% in Japan. It accounts for 50% of all dementias in Japan, 20% to 40% in
Europe and 15% in Latin America. The incidence of dementia is 9 times higher in patients who have had a
stroke than in controls. 25% of stroke patients develop new-onset dementia within 1 year of their stroke.
The relative risk of incident dementia is 5.5% within 4 years of suffering a stroke.
The prevalence of vascular dementia is higher in men than in women and it increases with age.
Mortality/morbidity
The 5-year survival rate is 39% for patients with vascular dementia compared with 75% for age-matched
controls. Vascular dementia is associated with a higher mortality than "Alzheimer's", presumably because of
the excess in cardiovascular risk factors.
Clinical presentation
Patients suffering from vascular dementia present with cognitive impairment, acutely or subacutely, after an
acute cerebrovascular event. After the onset a stepwise progression is typical. However stepwise progression
may not be observed in small vessel disease, Binswanger's disease or vascular dementia due to small lacunar
infarcts.
In small vessel disease the incidence peaks between the 4th and the 7th decades of life and 80% will have a
history of hypertension. Patients develop progressive cognitive, motor and behavioral signs and symptoms. A
significant proportion of them also develop affective symptoms. These changes occur over a period of 5–10
years. If the frontal lobes are affected, which is often the case, patients may present as apatheticor abulic. This
is often accompanied by problems with attention, orientation and urinary incontinence.
As already stated, small vessel disease and focal lesions often overlap, so these two patterns may be evident
in the same individual concurrently.
Rare genetic disorders which result in vascular lesions in the brain have other patterns of presentation. As a
rule of thumb they tend to present earlier in life and have a more aggressive course.
Diagnosis
Several specific diagnostic criteria can be used to diagnose vascular dementia, including the Diagnostic and
Statistical Manual of Mental Disorders, Fourth Edition (DSM-IV) criteria, the International Classification of
Diseases, Tenth Edition (ICD-10) criteria, the National Institute of Neurological Disorders and Stroke-
Association Internationale pour la Recherche et l'Enseignement en Neurosciences (NINDS-AIREN) criteria, the
Alzheimer's Disease Diagnostic and Treatment Center criteria, and the Hachinski ischemic score.
Lateralizing signs such as hemiparesis, bradykinesia, hyperreflexia, extensor plantar
reflexes, ataxia, pseudobulbar palsy, and gait andswallowing difficulties may be observed.
In terms of cognitive testing patients have patchy deficits. They tend to have better free recall and fewer recall
intrusions compared with patients with Alzheimer's disease. As small vessel disease often affects the frontal
lobes, apathy early in the disease is more suggestive of vascular dementia because it usually occurs in the
later stages of Alzheimer's. Consequently patients with vascular dementia perform worse than their Alzheimer's
disease counterparts in frontal lobe tasks such as verbal fluency. They also tend to exhibit more perseverative
behavior. They may also present with general slowing of processing ability, difficulty shifting sets and
impairment in abstract thinking. In the more severe patients, or those patients affected by strategic infarcts in
the Wernicke or Broca areas, dysarthrias, dysphasias and aphasias may be present.
Etiology
Risk factors for vascular dementia include hypertension, smoking, hypercholesterolemia, diabetes mellitus, and
cardiovascular and cerebrovascular disease.
Investigations
The recommended investigations for cognitive impairment should be carried out, including a dementia
screening blood test, chest X-Ray, CAT scan and EKG. The screening blood test should typically include full
blood count, liver function tests, thyroid function tests, lipid profile,erythrocyte sedimentation rate, C reactive
protein, syphilis serology, calcium serum level, fasting glucose, urea and electrolytes, vitamin B-12, folate. In
selected patients HIV serology and autoantibody testing may be done.
Treatment
The aim of the management is the prevention of further cerebrovascular lesions. This includes administering
antiplatelet drugs and controlling major vascular risk factors (hypertension, hypercholesterolemia, smoking and
diabetes mellitus to mention a few).
The general management of dementia includes referral to community services, judgment and decision-making
regarding legal and ethical issues (e.g., driving, capacity, advance directives), and consideration of caregiver
stress.
Cholinesterase inhibitors such as galantamine have shown to be helpful in various randomized controlled trials.
However their use is not licensed yet for this indication.
Behavioral and affective symptoms are particularly important in this patient group and deserve special
consideration. These problems, if they develop, tend to be resistant to conventional psychopharmacological
treatment and in many cases lead to hospital admission and placement in permanent care. Agents that may be
useful include antidepressants, neuroleptics and mood-stabilizers. Electroconvulsive therapy may be indicated
in extreme cases provided a medical contraindication does not exist.
Epilepsy

Epilepsy (from the Ancient Greek ἐπιληψία (epilēpsía) — "to seize") is a common chronicneurological
disorder characterized by recurrent unprovoked seizures. These seizures are transient signs and/or symptoms
of abnormal, excessive or synchronous neuronal activity in the brain. About 50 million people worldwide have
epilepsy, with almost 90% of these people being in developing countries. Epilepsy is more likely to occur in
young children, or people over the age of 65 years; however, it can occur at any time. As a consequence of
brain surgery, epileptic seizures may occur in recovering patients.
Epilepsy is usually controlled, but cannot be cured with medication, although surgery may be considered in
difficult cases. However, over 30% of people with epilepsy do not have seizure control even with the best
available medications. Not all epilepsy syndromes are lifelong – some forms are confined to particular stages of
childhood. Epilepsy should not be understood as a single disorder, but rather as syndromic with vastly
divergent symptoms but all involving episodic abnormal electrical activity in the brain.
Classification
Epilepsies are classified in five ways:
1. By their first cause (or etiology).
2. By the observable manifestations of the seizures, known as semiology.
3. By the location in the brain where the seizures originate.
4. As a part of discrete, identifiable medical syndromes.
5. By the event that triggers the seizures, as in primary reading epilepsy or musicogenic epilepsy.
In 1981, the International League Against Epilepsy (ILAE) proposed a classification scheme for individual
seizures that remains in common use. This classification is based on observation (clinical and EEG) rather than
the underlying pathophysiology or anatomy and is outlined later on in this article. In 1989, the ILAE proposed a
classification scheme for epilepsies and epileptic syndromes. This can be broadly described as a two-axis
scheme having the cause on one axis and the extent of localization within the brain on the other. Since 1997,
the ILAE have been working on a new scheme that has five axes:
1. ictal phenomenon, (pertaining to an epileptic seizure)
2. seizure type,
3. syndrome,
4. etiology,
5. impairment.
Seizure types
Seizure types are organized firstly according to whether the source of the seizure within the brain is localized
(partial or focal onset seizures) or distributed (generalized seizures). Partial seizures are further divided on the
extent to which consciousness is affected. If it is unaffected, then it is a simple partial seizure; otherwise it is
a complex partial (psychomotor) seizure. A partial seizure may spread within the brain - a process known
as secondary generalization. Generalized seizures are divided according to the effect on the body but all
involve loss of consciousness. These include absence (petit mal), myoclonic, clonic, tonic, tonic-clonic (grand
mal) and atonic seizures.
Children may exhibit behaviors that are easily mistaken for epileptic seizures but are not caused by epilepsy.
These include:
 Inattentive staring
 Benign shudders (among children younger than age 2, usually when they are tired or excited)
 Self-gratification behaviors (nodding, rocking, head banging)
 Conversion disorder (flailing and jerking of the head, often in response to severe personal stress such
as physical abuse)
Conversion disorder can be distinguished from epilepsy because the episodes never occur during sleep and do
not involve incontinence or self-injury.
Seizure types
The numerous epileptic seizure types are most commonly defined and grouped according to a scheme
proposed by the International League Against Epilepsy (ILAE) in 1981. Distinguishing between seizure
types is important since different types of seizure may have different causes, prognosis and treatments.
International classification of seizure types (1981)
This classification is based on observation (clinical and EEG) rather than the
underlying pathophysiology or anatomy.
I Partial seizures (Older term: focal seizures)
A Simple partial seizures - consciousness is not impaired
1 With motor signs
2 With sensory symptoms
3 With autonomic symptoms or signs
4 With psychic symptoms
B Complex partial seizures - consciousness is impaired (Older terms: temporal lobe or psychomotor
seizures)
1 Simple partial onset, followed by impairment of consciousness
2 With impairment of consciousness at onset
C Partial seizures evolving to secondarily generalized seizures
1 Simple partial seizures evolving to generalized seizures
2 Complex partial seizures evolving to generalized seizures
3 Simple partial seizures evolving to complex partial seizures evolving to generalized seizures
II Generalized seizures
A Absence seizures (Older term: petit mal)
1 Typical absence seizures
2 Atypical absence seizures
B Myoclonic seizures
C Clonic seizures
D Tonic seizures
E Tonic–clonic seizures (Older term: grand mal)
F Atonic seizures
III Unclassified epileptic seizures
In terms of their origin within the brain, seizures may be described as either partial (focal) or generalized.
Partial seizures only involve a localized part of the brain, whereas generalized seizures involve the whole of
both hemispheres. The term 'secondary generalisation' may be used to describe a partial seizure that later
spreads to the whole of the cortex and becomes generalized.
Whilst most seizures can be neatly split into partial and generalized, there exists some that don't fit. For
example: the seizure may be generalized only within one hemisphere. Alternatively there may be many focal
points (multifocal seizures) that are distributed in a symmetrical or asymmetrical pattern.
Partial seizures
Partial seizures may be further subdivided into both simple and complex seizures. This refers to the effect of
such a seizure onconsciousness; simple seizures cause no interruption to consciousness (although they may
cause sensory distortions or other sensations), whereas complex seizures interrupt consciousness to varying
degrees. This does not necessarily mean that the person experiencing this sort of seizure will fall unconscious
(like fainting). For example, a complex partial seizure may involve the unconscious repetition of simple
actions, gestures or verbal utterances, or simply a blank stare and apparent unawareness of the occurrence of
the seizure, followed by no memory of the seizure. Other patients may report a feeling of tunnel vision or
dissociation, which represents a diminishment of awareness without full loss of consciousness. Still other
patients can perform complicated actions, such as travel or shopping, while in the midst of a complex partial
seizure.
The effects of partial seizures can be quite dependent on the area of the brain in which they are active. For
example, a partial seizure in areas involved in perception may cause a particular sensory experience (for
example, the perception of a scent, music or flashes of light) whereas, when centred in the motor cortex, a
partial seizure might cause movement in particular groups of muscles. This type of seizure may also produce
particular thoughts or internal visual images or even experiences which may be distinct but not easily
described. Seizures centered on the temporal lobes are known to produce mystical or ecstatic experiences
in some people. These may result in a misdiagnosis ofpsychosis or even schizophrenia,[citation needed] if
other symptoms of seizure are disregarded and other tests are not performed. Unfortunately for those with
epilepsy, anti-psychotic medications prescribed without anticonvulsants in this case can actually lower the
seizure threshold further and worsen the symptoms.
When the effects of a partial seizure appear as a 'warning sign' before a larger seizure, they are known as
an aura: it is frequently the case that a partial seizure will spread to other parts of the brain and eventually
become generalized, resulting in a tonic-clonic convulsion. The subjective experience of an aura, like other
partial seizures, will tend to reflect the function of the affected part of the brain.
Generalized seizures
Primarily generalized seizures can be sub-classified into a number of categories, depending on their
behavioural effects:
 Absence seizures involve an interruption to consciousness where the person experiencing the
seizure seems to become vacant and unresponsive for a short period of time (usually up to 30
seconds). Slight muscle twitching may occur.
 Myoclonic seizures involve an extremely brief (< 0.1 second) muscle contraction and can result in
jerky movements of muscles or muscle groups.
 Clonic seizures are myoclonus that are regularly repeating at a rate typically of 2-3 per second.
 Tonic–clonic seizures involve an initial contraction of the muscles (tonic phase) which may
involve tongue biting, urinary incontinence and the absence of breathing. This is followed by
rhythmic muscle contractions (clonic phase). This type of seizure is usually what is referred to when
the term 'epileptic fit' is used colloquially.
 Atonic seizures involve the loss of muscle tone, causing the person to fall to the ground. These are
sometimes called 'drop attacks' but should be distinguished from similar looking attacks that may occur
in narcolepsy or cataplexy.
Mixed seizures
Mixed seizure is defined as the existence of both generalized and partial seizures in the same patient. For
example, someone who periodically has myoclonic seizures may have a tonic-clonic seizure triggered e.g.
by a mild fever.
Continuous seizures
Status epilepticus refers to continuous seizure activity with no recovery between successive seizures. When
the seizures are convulsive, it is a life-threatening condition and emergency medical assistance should be
called immediately if this is suspected. A tonic-clonic seizure lasting longer than 5 minutes (or two minutes
longer than a given person's usual seizures) is usually considered grounds for calling the emergency services.
Epilepsia partialis continua is a rare type of focal motor seizure (hands and face) which recurs every few
seconds or minutes for extended periods (days or years). It is usually due to strokes in adults and focal cortical
inflammatory processes in children (Rasmussen's encephalitis), possibly caused by chronic viral
infections or autoimmune processes.
Future classifications
In 1997, the ILAE began work on revising the classification of seizures, epilepsies and epileptic
syndromes. This revision remains in gestation and has not superseded the 1981 classification.
Proposed changes to terminology include:
 Replace partial with the older term focal to describe seizures that originate in one part of the brain
(though not necessarily a small or well defined area). The word partial was regarded as ambiguous.
 Drop the terms simple partial and complex partial - grouping based on the effect to consciousness is
no longer regarded as useful.
 Replace cryptogenic with probably symptomatic.
The hierarchy presented has the structure:
Self limiting seizure types
Generalized seizures
Tonic-clonic seizures (includes variations beginning with a clonic or myoclonic phase)
Clonic seizures (with and without tonic features)
Typical absence seizures
Atypical absence seizures
Myoclonic absence seizures
Tonic seizures
Spasms
Myoclonic seizures
Massive bilateral myoclonus
Eyelid myoclonia (with and without absences)
Myoclonic atonic seizures
Negative myoclonus
Atonic seizures
Reflex seizures in generalized epilepsy syndromes
Seizures of the posterior neocortex
Neocortical temporal lobe seizures
Focal seizures
Focal sensory seizures
Focal motor seizures
Gelastic seizures
Hemiclonic seizures
Secondarily generalized seizures
Reflex seizures in focal epilepsy syndromes
Continuous seizure types
Generalized status epilepticus
Generalized tonic-clonic status epilepticus
Clonic status epilepticus
Absence status epilepticus
Tonic status epilepticus
Myoclonic status epilepticus
Focal status epilepticus
Epilepsia partialis continua of Kojevnikov
Aura continua
Limbic status epilepticus (psychomotor status)
Hemiconvulsive status with hemiparesis
Earlier classifications
The 1981 classification was a revision of the one devised by Henri Gastaut for the ILAE and published in
1970. A significant difference was the distinction between simple and complex partial seizures. In the 1970
classification, the distinction was whether the symptoms involved elementary sensory or motor functions
(simple) or whether "higher functions" were involved (complex). This was changed to consider whether
consciousness was fully retained or not. As a result, studies that group patients according to these
classifications are not directly comparable from one generation to another. The 1970 classification was
important for standardising the modern terms for many seizure types. Prior to this, terms such as petit
mal, grand mal, Jacksonian, psychomotor and temporal-lobe seizures were used.
The earliest classification of seizures can be attributed to Babylonian scholars who inscribed their medical
knowledge into stone tablets know as the Sakikku (meaning All Diseases). This dates from the reign of
the Babylonian king Adad-apla-iddina of the Second Dynasty of Isin - estimated to be between 1067 and
1046 BC. Many types of seizures are described, each attributed to a certain demon or departed spirit and
given a prognosis.

Epilepsy syndromes
There are over 40 different types of epilepsy, including: Absence seizures, atonic seizures, benign Rolandic
epilepsy, childhood absence,clonic seizures, complex partial seizures, frontal lobe epilepsy, febrile
seizures, infantile spasms, juvenile myoclonic epilepsy, juvenile absence epilepsy, hot water epilepsy, Lennox-
Gastaut syndrome, Landau-Kleffner syndrome , myoclonic seizures, mitochondrial disorders,progressive
myoclonic epilepsy, psychogenic seizures, reflex epilepsy, Rasmussen's syndrome, simple partial seizures,
secondarily generalized seizures, temporal lobe epilepsy, tonic-clonic seizures, tonic seizures, psychomotor
seizures, limbic epilepsy, partial-onset seizures, Rett syndrome, generalized-onset seizures, status
epilepticus, abdominal epilepsy, akinetic seizures, autonomic seizures, massive
bilateral myoclonus, catamenial epilepsy, drop seizures, emotional seizures, focal seizures, gelastic seizures,
Jacksonian seizure disorder, Lafora disease, motor seizures, multifocal seizures, neonatal seizures, nocturnal
seizures, photosensitive epilepsy,pseudoseizures, sensory seizures, subtle seizures, Sylvan
seizures, withdrawal seizures and visual reflex seizures, among others.
Each type of epilepsy presents with its own unique combination of seizure type, typical age of onset, EEG
findings, treatment, and prognosis. The most widespread classification of the epilepsies divides epilepsy
syndromes by location or distribution of seizures (as revealed by the appearance of the seizures and by EEG)
and by cause. Syndromes are divided into localization-related epilepsies, generalized epilepsies, or epilepsies
of unknown localization.
Localization-related epilepsies, sometimes termed partial or focal epilepsies, arise from an epileptic focus, a
small portion of the brain that serves as the irritant driving the epileptic response. Generalized epilepsies, in
contrast, arise from many independent foci (multifocal epilepsies) or from epileptic circuits that involve the
whole brain. Epilepsies of unknown localization remain unclear whether they arise from a portion of the brain or
from more widespread circuits.
Epilepsy syndromes are further divided by presumptive cause: idiopathic, symptomatic, and cryptogenic.
Idiopathic epilepsies are generally thought to arise from genetic abnormalities that lead to alteration of basic
neuronal regulation. Symptomatic epilepsies arise from the effects of an epileptic lesion, whether that lesion is
focal, such as a tumor, or a defect in metabolism causing widespread injury to the brain. Cryptogenic epilepsies
involve a presumptive lesion that is otherwise difficult or impossible to uncover during evaluation.
The genetic component to epilepsy is receiving particular interest from the scientific community. Conditions
such as ring chromosome 20 syndrome (r(20))are gaining acknowledgment, and although only 60 cases have
been reported in the literature since 1976, "more widespread cytogenetic chromosomal karyotyping in
nonetiological cases of epilepsy" is likely.
Some epileptic syndromes are difficult to fit within this classification scheme and fall in the unknown
localization/etiology category. People who only have had a single seizure, or those with seizures that occur
only after specific precipitants ("provoked seizures"), have "epilepsies" that fall into this category. Febrile
convulsions are an example of seizures bound to a particular precipitant. Landau-Kleffner syndrome is another
epilepsy which, because of its variety of EEG distributions, falls uneasily in clear categories. More confusingly,
certain syndromes,such as West syndrome, featuring seizures such as infantile spasms can be classified as
idiopathic, syndromic, or cryptogenic depending on cause and can arise from both focal or generalized epileptic
lesions.
Below are some common seizure syndromes:
 Autosomal dominant nocturnal frontal lobe epilepsy (ADNFLE) is an idiopathic localization-related
epilepsy that is an inherited epileptic disorder that causes seizures during sleep. Onset is usually in
childhood. These seizures arise from the frontal lobes and consist of complex motor movements, such as
hand clenching, arm raising/lowering, and knee bending. Vocalizations such as shouting, moaning, or
crying are also common. ADNFLE is often misdiagnosed as nightmares. ADNFLE has a genetic
basis. These genes encode various nicotinic acetylcholine receptors.
 Benign centrotemporal lobe epilepsy of childhood or benign Rolandic epilepsy is an idiopathic
localization-related epilepsy that occurs in children between the ages of 3 and 13 years, with peak onset in
prepubertal late childhood. Apart from their seizure disorder, these patients are otherwise normal. This
syndrome features simple partial seizures that involve facial muscles and frequently cause drooling.
Although most episodes are brief, seizures sometimes spread and generalize. Seizures are typically
nocturnal and confined to sleep. The EEG may demonstrate spike discharges that occur over the
centrotemporal scalp over the central sulcus of the brain (the Rolandic sulcus) that are predisposed to
occur during drowsiness or light sleep. Seizures cease near puberty. Seizures may
requireanticonvulsant treatment, but sometimes are infrequent enough to allow physicians to defer
treatment.
 Benign occipital epilepsy of childhood (BOEC) is an idiopathic localization-related epilepsy and
consists of an evolving group of syndromes. Most authorities include two subtypes, an early subtype with
onset between three and five years, and a late onset between seven and 10 years. Seizures in BOEC
usually feature visual symptoms such as scotoma or fortifications (brightly colored spots or lines) or
amaurosis (blindness or impairment of vision). Convulsions involving one half the body, hemiconvulsions,
or forced eye deviation or head turning are common. Younger patients typically experience symptoms
similar to migraine with nausea and headache, and older patients typically complain of more visual
symptoms. The EEG in BOEC shows spikes recorded from the occipital (back of head) regions. The EEG
and genetic pattern suggest an autosomal dominant transmission as described by Ruben Kuzniecky, et
al. Lately, a group of epilepsies termed Panayiotopoulos syndrome that share some clinical features of
BOEC but have a wider variety of EEG findings are classified by some as BOEC.
 Catamenial epilepsy (CE) is when seizures cluster around certain phases of a woman's menstrual
cycle.
 Childhood absence epilepsy (CAE) is an idiopathic generalized epilepsy that affects children
between the ages of four and 12 years of age, although peak onset is around five to six years old. These
patients have recurrent absence seizures, brief episodes of unresponsive staring, sometimes with minor
motor features such as eye blinking or subtle chewing. The EEG finding in CAE is generalized 3 Hz spike
and wave discharges. Some go on to develop generalized tonic-clonic seizures. This condition carries a
good prognosis because children do not usually show cognitive decline or neurological deficits, and the
seizures in the majority cease spontaneously with onging maturation.
 Dravet's syndrome, previously known as severe myoclonic epilepsy of infancy (SMEI), is a
neurodevelopmental disorder beginning in infancy and characterized by severe epilepsy that does not
respond well to treatment. This syndrome was described by Charlotte Dravet, French psychiatrist and
epileptologist (born July 14, 1936). Dravet described this syndrome while working at the Centre Saint Paul
at the University of Marseille. At Centre Saint Paul, one of her supervisors was Henri Gastaut, who
described the Lennox-Gastaut syndrome. She described this condition in 1978 Estimates of the
prevalence of this rare disorder have ranged from 1:20,000 to 1:40,000 births, though the incidence may
be found to be greater as the syndrome becomes better recognized and new genetic evidence is
discovered. It is thought to occur with similar frequency in both genders, and knows no geographic or
ethnic boundaries.
The course of Dravet syndrome is highly variable from person to person. Seizures begin during the
first year of life and development is normal prior to their onset. In most cases, the first seizures occur
with fever and are generalized tonic-clonic (grand mal) or unilateral (one-sided) convulsions. These
seizures are often prolonged, and may lead to status epilepticus, a medical emergency. In time,
seizures increase in frequency and begin to occur without fever. Additional seizure types appear, most
often these are myoclonic, atypical absence, and complex-partial seizures.
Additional features that are seen in significant numbers of patients with Dravet syndrome may
include sensory integration disorders and other autism spectrum characteristics, orthopedic or
movement disorders, frequent or chronic upper respiratory and ear infections, sleep
disturbance, dysautonomia, and problems with growth and nutrition.
 Frontal lobe epilepsy, usually a symptomatic or cryptogenic localization-related epilepsy, arises from
lesions causing seizures that occur in the frontal lobes of the brain. These epilepsies can be difficult to
diagnose because the symptoms of seizures can easily be confused with nonepileptic spells and, because
of limitations of the EEG, be difficult to "see" with standard scalp EEG.
 Juvenile absence epilepsy is an idiopathic generalized epilepsy with later onset than CAE, typically
in prepubertal adolescence, with the most frequent seizure type being absence seizures. Generalized
 tonic-clonic seizures can occur. Often, 3 Hz spike-wave or multiple spike discharges can be seen on EEG.
The prognosis is mixed, with some patients going on to a syndrome that is poorly distinguishable from
JME.
 Juvenile myoclonic epilepsy (JME) is an idiopathic generalized epilepsy that occurs in patients aged
8 to 20 years. Patients have normal cognition and are otherwise neurologically intact. The most common
seizures are myoclonic jerks, although generalized tonic-clonic seizures and absence seizures may occur
as well. Myoclonic jerks usually cluster in the early morning after awakening. The EEG reveals generalized
4–6 Hz spike wave discharges or multiple spike discharges. Interestingly, these patients are often first
diagnosed when they have their first generalized tonic-clonic seizure later in life, when they experience
sleep deprivation (e.g., freshman year in college after staying up late to study for exams). Alcohol
withdrawal can also be a major contributing factor in breakthrough seizures, as well. The risk of the
tendency to have seizures is lifelong; however, the majority have well-controlled seizures with
anticonvulsant medication and avoidance of seizure precipitants.
 Lennox-Gastaut syndrome (LGS) is a generalized epilepsy that consists of a triad of developmental
delay or childhood dementia, mixed generalized seizures, and EEG demonstrating a pattern of
approximately 2 Hz "slow" spike-waves. Onset occurs between two and 18 years. As in West syndrome,
LGS result from idiopathic, symptomatic, or cryptogenic causes, and many patients first have West
syndrome. Authorities emphasize different seizure types as important in LGS, but most have astatic
seizures (drop attacks), tonic seizures, tonic-clonic seizures, atypical absence seizures, and sometimes,
complex partial seizures. Anticonvulsants are usually only partially successful in treatment.
 Ohtahara syndrome is a rare, but mild, form of epilepsy syndrome combined with cerebral palsy, and
characterised with frequent seizures which typically start in the first few days of life.
 Primary reading epilepsy is a reflex epilepsy classified as an idiopathic localization-related epilepsy.
Reading in susceptible individuals triggers characteristic seizures.
 Progressive myoclonic epilepsies define a group of symptomatic generalized epilepsies
characterized by progressive dementia and myoclonic seizures. Tonic-clonic seizures may occur as well.
Diseases usually classified in this group are Unverricht-Lundborg disease, myoclonus epilepsy with ragged
red fibers (MERRF syndrome), Lafora disease, neuronal ceroid lipofucinosis, and sialdosis.
 Rasmussen's encephalitis is a symptomatic localization-related epilepsy that is a progressive,
inflammatory lesion affecting children with onset before the age of 10. Seizures start as separate simple
partial or complex partial seizures and may progress to epilepsia partialis continua (simple partial status
epilepticus). Neuroimaging shows inflammatory encephalitis on one side of the brain that may spread if not
treated. Dementia and hemiparesis are other problems. The cause is hypothesized to involve an
immulogical attack against glutamate receptors, a common neurotransmitter in the brain.
 Symptomatic localization-related epilepsies are divided by the location in the brain of the epileptic
lesion, since the symptoms of the seizures are more closely tied to the brain location rather than the cause
of the lesion. Tumors, atriovenous malformations, cavernous malformations, trauma, and cerebral infarcts
can all be causes of epileptic foci in different brain regions.
 Temporal lobe epilepsy (TLE), a symptomatic localization-related epilepsy, is the most common
epilepsy of adults who experience seizures poorly controlled with anticonvulsant medications. In most
cases, the epileptogenic region is found in the midline (mesial) temporal structures (e.g.,
the hippocampus, amygdala, and parahippocampal gyrus). Seizures begin in late childhood and
adolescence. Most of these patients have complex partial seizures sometimes preceded by an aura, and
some TLE patients also suffer from secondary generalized tonic-clonic seizures. If the patient does not
respond sufficiently to medical treatment, epilepsy surgery may be considered.
 Tuberous Sclerosis (TSC) is a genetic disorder that causes tumors to form in many different organs,
primarily in the brain, eyes, heart, kidney, skin and lungs. Several types of brain lesions can occur in
individuals with TSC and 60% - 90% of people with TSC develop epilepsy.
 West syndrome is a triad of developmental delay, seizures termed infantile spasms,
and EEG demonstrating a pattern termedhypsarrhythmia. Onset occurs between three months and two
years, with peak onset between eight and 9 months. West syndrome may arise from idiopathic,
symptomatic, or cryptogenic causes. The most common cause is tuberous sclerosis. The prognosis varies
with the underlying cause. In general, most surviving patients remain with significant cognitive impairment
and continuing seizures and may evolve to another eponymic syndrome, Lennox-Gastaut syndrome.
Causes
The diagnosis of epilepsy usually requires that the seizures occur spontaneously. Nevertheless, certain
epilepsy syndromes require particular precipitants or triggers for seizures to occur. These are termed reflex
epilepsy. For example, patients with primary reading epilepsy have seizures triggered by
reading. Photosensitive epilepsy can be limited to seizures triggered by flashing lights. Other precipitants
can trigger an epileptic seizure in patients who otherwise would be susceptible to spontaneous seizures.
For example, children with childhood absence epilepsy may be susceptible to hyperventilation. In fact,
flashing lights and hyperventilation are activating procedures used in clinical EEG to help trigger seizures
to aid diagnosis. Finally, other precipitants can facilitate, rather than obligately trigger, seizures in
susceptible individuals. Emotional stress, sleep deprivation, sleep itself, heat stress, alcohol and febrile
illness are examples of precipitants cited by patients with epilepsy. Notably, the influence of various
 precipitants varies with the epilepsy syndrome. Likewise, the menstrual cycle in women with epilepsy can
influence patterns of seizure recurrence. Catamenial epilepsy is the term denoting seizures linked to
the menstrual cycle.
There are different causes of epilepsy that are common in certain age groups.
 During the neonatal period and early infancy the most common causes include hypoxic-ischemic
encephalopathy, CNS infections, trauma, congenital CNS abnormalities, and metabolic disorders.
 During late infancy and early childhood, febrile seizures are fairly common. These may be caused by
many different things, some thought to be things such as CNS infections and trauma.
 During childhood, well-defined epilepsy syndromes are generally seen.
 During adolescence and adulthood, the causes are more likely to be secondary to any CNS lesion.
Further, idiopathic epilepsy is less common. Other causes associated with these age groups are stress,
trauma, CNS infections, brain tumors, illicit drug use and alcohol withdrawal.
 In older adults, cerebrovascular disease is a very common cause. Other causes are CNS tumors,
head trauma, and other degenerative diseases which are common in the older age group, such
as dementia.
Pathophysiology
Mutations in several genes have been linked to some types of epilepsy. Several genes that code
for protein subunits of voltage-gated andligand-gated ion channels have been associated with forms of
generalized epilepsy and infantile seizure syndromes. Several ligand-gated ion channels have been linked
to some types of frontal and generalized epilepsies. One speculated mechanism for some forms of
inherited epilepsy are mutations of the genes which code for sodium channel proteins; these defective
sodium channels stay open for too long thus making the neuron hyper-excitable. Glutamate, an excitatory
neurotransmitter, may thereby be released from these neurons in large amounts which—by binding with
nearby glutamatergic neurons—triggers excessive calcium (Ca 2+) release in these post-synaptic cells.
Such excessive calcium release can be neurotoxic to the affected cell. The hippocampus, which contains a
large volume of just such glutamanergic neurons (and NMDA receptors, which are permeable to Ca 2+ entry
after binding of both sodium and glutamate), is especially vulnerable to epileptic seizure, subsequent
spread of excitation, and possible neuronal death. Another possible mechanism involves mutations leading
to ineffective GABA (the brain's most common inhibitory neurotransmitter) action. Epilepsy-related
mutations in some non-ion channel genes have also been identified.
Epileptogenesis is the process by which a normal brain develops epilepsy after an insult. One interesting
finding in animals is that repeated low-level electrical stimulation to some brain sites can lead to permanent
increases in seizure susceptibility: in other words, a permanent decrease in seizure "threshold." This
phenomenon, known as kindling (by analogy with the use of burning twigs to start a larger fire) was
discovered by Dr. Graham Goddard in 1967. It is important to note that these "kindled" animals do not
experience spontaneous seizures. Chemical stimulation can also induce seizures; repeated exposures to
some pesticides have been shown to induce seizures in both humans and animals. One mechanism
proposed for this is called excitotoxicity. The roles of kindling and excitotoxicity, if any, in human epilepsy
are currently hotly debated.
Other causes of epilepsy are brain lesions, where there is scar tissue or another abnormal mass of tissue in an
area of the brain.
The complexity of understanding what seizures are have led to considerable efforts to use computational
models of epilepsy to both interpret experimental and clinical data, as well as guide strategies for therapy.
Management
Epilepsy is usually treated with medication prescribed by a physician; primary caregivers, neurologists,
and neurosurgeons all frequently care for people with epilepsy. However, it has been stressed that
accurate differentiation between generalized and partial seizures is especially important in determining the
appropriate treatment. In some cases the implantation of a stimulator of the vagus nerve, or a special diet
can be helpful. Neurosurgical operations for epilepsy can be palliative, reducing the frequency or severity
of seizures; or, in some patients, an operation can be curative.
The proper initial response to a generalized tonic-clonic epileptic seizure is to prevent the person from self-
injury by moving them away from sharp edges, placing something soft beneath the head, and rolling the
person into the recovery position. Should the person regurgitate, this should be allowed to drip out the side
of the person's mouth. If a seizure lasts longer than 5 minutes, or if more than one seizure occurs without
regaining consciousness emergency medical services should be contacted.
Medications
Anticonvulsant
The mainstay of treatment of epilepsy is anticonvulsant medications. Often, anticonvulsant medication
treatment will be lifelong and can have major effects on quality of life. The choice among anticonvulsants
and their effectiveness differs by epilepsy syndrome. Mechanisms, effectiveness for particular epilepsy
syndromes, and side effects differ among the individual anticonvulsant medications. Some general findings
about the use of anticonvulsants are outlined below.
Availability- Currently there are 20 medications approved by the Food and Drug Administration for the use of
treatment of epileptic seizures in the US: carbamazepine (common US brand name
 Tegretol), clorazepate (Tranxene), clonazepam (Klonopin), ethosuximide (Zarontin),felbamate (Felbatol), fo
sphenytoin (Cerebyx), gabapentin (Neurontin), lacosamide (Vimpat), lamotrigine (Lamictal), levetiracetam (
Keppra),oxcarbazepine (Trileptal), phenobarbital (Luminal), phenytoin (Dilantin), pregabalin (Lyrica), primid
one (Mysoline), tiagabine (Gabitril),topiramate (Topamax), valproate semisodium (Depakote), valproic
acid (Depakene), and zonisamide (Zonegran). Most of these appeared after 1990.
Medications commonly available outside the US but still labelled as "investigational" within the US
are clobazam (Frisium) and vigabatrin(Sabril). Medications currently under clinical trial under the
supervision of the FDA include retigabine, brivaracetam, and seletracetam.
Other drugs are commonly used to abort an active seizure or interrupt a seizure flurry; these
include diazepam (Valium, Diastat) andlorazepam (Ativan). Drugs used only in the treatment of
refractory status epilepticus include paraldehyde (Paral), midazolam (Versed),
andpentobarbital (Nembutal).
Some anticonvulsant medications do not have primary FDA-approved uses in epilepsy but are used in limited
trials, remain in rare use in difficult cases, have limited "grandfather" status, are bound to particular severe
epilepsies, or are under current investigation. These
includeacetazolamide (Diamox), progesterone, adrenocorticotropic hormone (ACTH, Acthar), various
corticotropic steroid hormones (prednisone), orbromide.
Effectiveness - The definition of "effective" varies. FDA-approval usually requires that 50% of the patient
treatment group had at least a 50% improvement in the rate of epileptic seizures. About 20% of patients
with epilepsy continue to have breakthrough epileptic seizures despite best anticonvulsant treatment.
Safety and Side Effects - 88% of patients with epilepsy, in a European survey, reported at least one
anticonvulsant related side [Link] side effects are mild and "dose-related" and can often be avoided
or minimized by the use of the smallest effective amount. Some examples include mood changes,
sleepiness, or unsteadiness in gait. Some anticonvulsant medications have "idiosyncratic" side effects that
can not be predicted by dose. Some examples include drug rashes, liver toxicity (hepatitis), or aplastic
anemia. Safety includes the consideration of teratogenicity (the effects of medications on fetal
development) when women with epilepsy become pregnant.
Principles of Anticonvulsant Use and Management - The goal for individual patients is, no seizures and
minimal side effects, and the job of the physician is to aid the patient to find the best balance between the
two during the prescribing of anticonvulsants. Most patients can achieve this balance best
with monotherapy, the use of a single anticonvulsant medication. Some patients, however,
require polypharmacy; the use of two or more anticonvulsants.
Serum levels of AEDs can be checked to determine medication compliance, to assess the effects of new drug-
drug interactions upon previous stable medication levels, or to help establish if particular symptoms such
as instability or sleepiness can be considered a drug side effect or are due to different causes. Children or
impaired adults who may not be able to communicate side effects may benefit from routine screening of
drug levels. Beyond baseline screening, however, trials of recurrent, routine blood or urine monitoring
show no proven benefits and may lead to unnecessary medication adjustments in most older children and
adults using routine anticonvulsants.
If a person's epilepsy cannot be brought under control after adequate trials of two or three (experts vary here)
different drugs, that person's epilepsy is generally said to be medically refractory. A study of patients with
previously untreated epilepsy demonstrated that 47% achieved control of seizures with the use of their first
single drug. 14% became seizure free during treatment with a second or third drug. An additional 3%
became seizure-free with the use of two drugs simultaneously. Other treatments, in addition to or instead
of, anticonvulsant medications may be considered by those people with continuing seizures.
Surgery
Epilepsy surgery is an option for patients whose seizures remain resistant to treatment with anticonvulsant
medications who also have symptomatic localization-related epilepsy; a focal abnormality that can be
located and therefore removed. The goal for these procedures is total control of epileptic
seizures, although anticonvulsant medications may still be required.
The evaluation for epilepsy surgery is designed to locate the "epileptic focus" (the location of the epileptic
abnormality) and to determine if resective surgery will affect normal brain function. Physicians will also
confirm the diagnosis of epilepsy to make sure that spells arise from epilepsy (as opposed to non-epileptic
seizures). The evaluation typically includes neurological examination, routine EEG, Long-term video-EEG
monitoring, neuropsychological evaluation, and neuroimaging such as MRI, Single photon emission
computed tomography (SPECT),positron emission tomography (PET). Some epilepsy centers
use intracarotid sodium amobarbital test (Wada test), functional MRI orMagnetoencephalography (MEG)
as supplementary tests.
Certain lesions require Long-term video-EEG monitoring with the use of intracranial electrodes if noninvasive
testing was inadequate to identify the epileptic focus or distinguish the surgical target from normal brain
tissue and function. Brain mapping by the technique of cortical electrical stimulation
or Electrocorticography are other procedures used in the process of invasive testing in some patients.
The most common surgeries are the resection of lesions like tumors or arteriovenous malformations which, in
the process of treating the underlying lesion, often result in control of epileptic seizures caused by these
lesions.
Other lesions are more subtle and feature epilepsy as the main or sole symptom. The most common form of
intractable epilepsy in these disorders in adults is temporal lobe epilepsy with hippocampal sclerosis, and
the most common type of epilepsy surgery is the anterior temporal lobectomy, or the removal of the front
portion of the temporal lobe including the amygdala and hippocampus. Some neurosurgeons recommend
selective amygdalahippocampectomy because of possible benefits in postoperative memory or language
function. Surgery for temporal lobe epilepsy is effective, durable, and results in decreased health care
costs. Despite the efficacy of epilepsy surgery, some patients decide not to undergo surgery owing to fear
or the uncertainty of having a brain operation.
Palliative surgery for epilepsy is intended to reduce the frequency or severity of seizures. Examples
are callosotomy or commissurotomy to prevent seizures from generalizing (spreading to involve the entire
brain), which results in a loss of consciousness. This procedure can therefore prevent injury due to the
person falling to the ground after losing consciousness. It is performed only when the seizures cannot be
controlled by other means. Multiple subpial transection can also be used to decrease the spread of
seizures across the cortex especially when the epileptic focus is located near important functional areas of
the cortex. Resective surgery can be considered palliative if it is undertaken with the expectation that it will
reduce but not eliminate seizures.
Hemispherectomy involves removal or a functional disconnection of most or all of one half of the cerebrum. It is
reserved for people suffering from the most catastrophic epilepsies, such as those due to Rasmussen
syndrome. If the surgery is performed on very young patients (2–5 years old), the remaining hemisphere
may acquire some rudimentary motor control of the ipsilateral body; in older patients, paralysis results on
the side of the body opposite to the part of the brain that was removed. Because of these and other side
effects it is usually reserved for patients who have exhausted other treatment options.
Other
A ketogenic diet (high fat, low carbohydrate) was developed in the 1920s, and was largely forgotten with the
advent of effectiveanticonvulsants, but was resurrected in the 1990s. The mechanism of action is
unknown. It is used mainly in the treatment of children with severe, medically intractable epilepsies, and
the New York Times reported that use is supported by peer-reviewed research that found that the diet
reduced seizures among drug-resistant epileptics by >50% in 38% of patients and by >90% in 7% of
patients.
While far from a cure, operant-based biofeedback based on conditioning of EEG waves has some
experimental support (see Professional practice of behavior analysis). Overall, the support is based on a
handful of studies reviewed by Barry Sterman. These studies report a 30% reduction in weekly seizures.
Electrical stimulation methods of anticonvulsant treatment are both currently approved for treatment and
investigational uses. A currently approved device is vagus nerve stimulation (VNS). Investigational devices
include the responsive neurostimulation system (RNS) and deep brain stimulation (DBS).
 Vagus nerve stimulation (US manufacturer Cyberonics) consists of a computerized electrical device
similar in size, shape and implant location to a heart pacemaker that connects to the vagus nerve in
the neck. The device stimulates the vagus nerve at preset intervals and intensities of current. Efficacy has
been tested in patients with localization-related epilepsies, demonstrating 50% of patients experience a
50% improvement in seizure rate. Case series have demonstrated similar efficacies in certain generalized
epilepsies, such as Lennox-Gastaut syndrome. Although success rates are not usually equal to that of
epilepsy surgery, it is a reasonable alternative when the patient is reluctant to proceed with any required
invasive monitoring, when appropriate presurgical evaluation fails to uncover the location of epileptic foci,
or when there are multiple epileptic foci.
 Responsive neurostimulator system (US manufacturer Neuropace) consists of a computerized
electrical device implanted in the skull, with electrodes implanted in presumed epileptic foci within the
brain. The brain electrodes send EEG signals to the device which contains seizure-detection software.
When certain EEG seizure criteria are met, the device delivers a small electrical charge to other electrodes
near the epileptic focus, which disrupt the seizure. The efficacy of the RNS is under current investigation
with the goal of FDA approval.
 Deep brain stimulation (US manufacturer Medtronic) consists of a computerized electrical device
implanted in the chest in a manner similar to the VNS, but electrical stimulation is delivered to deep brain
structures through depth electrodes implanted through the skull. In epilepsy, the electrode target is
the anterior nucleus of the thalamus. The efficacy of the DBS in localization-related epilepsies is currently
under investigation.
Noninvasive surgery using the gamma knife or other devices used in radiosurgery is currently being
investigated as analternative to traditional open surgery in patients who would otherwise qualify for anterior
temporal lobectomy.
Avoidance therapy consists of minimizing or eliminating triggers in patients whose seizures are particularly
susceptible to seizure precipitants (see above). For example, sunglasses that counter exposure to
particular light wavelengths can improve seizure control in certain photosensitive epilepsies.
Canine warning system is where a seizure response dog, a form of service dog, is trained to summon help or
ensure personal safety when a seizure occurs. These are not suitable for everybody, and not all dogs can
be so trained. Rarely, a dog may develop the ability to sense a seizure before it occurs. Development of
electronic forms of seizure detection systems are currently under investigation.
Seizure prediction-based devices using long-term EEG recordings is presently being evaluated as a new
way to stop epileptic seizures before they appear clinically.
Alternative or complementary medicine,
including acupuncture, psychological interventions, vitamins and yoga, was evaluated in a number
of systematic reviews by the Cochrane Collaboration into treatments for epilepsy, and found there is no
reliableevidence to support the use of these as treatments for epilepsy. Exercise or other physical
activity have also been proposed as efficacious strategies for preventing or treating epilepsy.
The Memorial Sloan-Kettering Cancer Center says dimethylglycine dietary supplement (DMG) will
"enhance oxygen utilization during hypoxia, reduce lactic acid build-up in the blood during stressful
events," and reduce the number of seizures experienced in epilepsy.
Epidemiology

Disability-adjusted life year for epilepsy per 100,000 inhabitants in 2002.

no data less than 50 50-72.5 72.5-95 95-117.5 117.5-140 140-162.5 162.5-185 185-207.5 207.5-230 230-
252.5 252.5-275 more than 275
Epilepsy is one of the most common of the serious neurological disorders. Genetic, congenital,
and developmental conditions are mostly associated with it among younger patients; tumors are more
likely over age 40; head trauma and central nervous system infections may occur at any age.
The prevalence of active epilepsy is roughly in the range 5–10 per 1000 people. Up to 5% of people
experience non febrile seizures at some point in life; epilepsy's lifetime prevalence is relatively high
because most patients either stop having seizures or (less commonly) die of it. Epilepsy's approximate
annual incidence rate is 40–70 per 100,000 in industrialized countries and 100–190 per 100,000 in
resource-poor countries; socioeconomically deprived people are at higher risk. In industrialized countries
the incidence rate decreased in children but increased among the elderly during the three decades prior to
2003, for reasons not fully understood.
Beyond symptoms of the underlying diseases that can be a part of certain epilepsies, people with epilepsy are
at risk for death from four main problems: status epilepticus (most often associated
with anticonvulsant noncompliance), suicide associated with depression, trauma from seizures, and
sudden unexpected death in epilepsy (SUDEP) Those at highest risk for epilepsy-related deaths usually
have underlying neurological impairment or poorly controlled seizures; those with more benign epilepsy
syndromes have little risk for epilepsy-related death.
The NICE National Sentinel Audit of Epilepsy-Related Deaths, led by "Epilepsy Bereaved" drew attention to
this important problem. The Audit revealed; "1,000 deaths occur every year in the UK as a result of
epilepsy" and most of them are associated with seizures and 42% of deaths were potentially avoidable".
Certain diseases also seem to occur in higher than expected rates in people with epilepsy, and the risk of these
"comorbidities" often varies with the epilepsy syndrome. These diseases include depression and anxiety
disorders, migraine and other headaches, infertility and low sexual libido. Attention-deficit/hyperactivity
disorder (ADHD) affects three to five times more children with epilepsy than children in the general
population. Epilepsy is prevalent in autism.
History
The word epilepsy is derived from the Ancient Greek ἐπιληψία epilēpsía, which was from
ἐπιλαμβάνειν epilambánein "to take hold of", which in turn was combined from ἐπί epí "upon" and
λαμβάνειν lambánein "to take". In the past, epilepsy was associated with religiousexperiences and
even demonic possession. In ancient times, epilepsy was known as the "Sacred Disease" because people
thought that epileptic seizures were a form of attack by demons, or that the visions experienced by persons
with epilepsy were sent by the gods. Amonganimist Hmong families, for example, epilepsy was understood
as an attack by an evil spirit, but the affected person could become revered as a shaman through these
otherworldly experiences.
However, in most cultures, persons with epilepsy have been stigmatized, shunned, or even imprisoned; in
the Salpêtrière, the birthplace of modern neurology, Jean-Martin Charcot found people with epilepsy side-
by-side with the mentally retarded, those with chronic syphilis, and the criminally insane. In Tanzania to
this day, as with other parts of Africa, epilepsy is associated with possession by evil spirits, witchcraft, or
poisoning and is believed by many to be contagious. In ancient Rome, epilepsy was known as the Morbus
Comitialis ('disease of the assembly hall') and was seen as a curse from the gods.
Stigma continues to this day, in both the public and private spheres, but polls suggest it is generally decreasing
with time, at least in the developed world; Hippocrates remarked that epilepsy would cease to be
considered divine the day it was understood.
Society and culture
Legal implications
Many jurisdictions forbid certain activities to persons suffering from epilepsy. The most commonly prohibited
activities involve operation of vehicles or machinery, or other activities in which continuous vigilance is
required. However, there are usually exceptions for those who can prove that they have stabilized their
condition. Those few whose seizures do not cause impairment of consciousness, have a lengthy aura
preceding impairment of consciousness, or whose seizures only arise from sleep, may be exempt from
such restrictions, depending on local laws. There is an ongoing debate in bioethics over who should bear
the burden of ensuring that an epilepsy patient does not drive a car or fly an airplane.