NEUROLOGY

For undergraduate

Prepared by
Neurology staff members
Neuropsychiatry department
Menoufia medical school

2014

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Contributors

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 CONTENTS

Introduction & Anatomy……………………………………………………………..

The Cranial Nerves…………………………………………………..

Language and Speech disorders …………………………………………

Blood supply of the brain……………………………………………..

Vascular Diseases of the nervous system…………………………

Paraplegia………………………………………………………………

Neurogenic Bladder………………………………………………….

Disorders of the Peripheral nerves……………………………………

Disorders of the skeletal muscles……………………………………

Disorders of the neuromuscular transmission……………………………

Ataxia & cerebellar Disorders……………………………………

Movement Disorders……………………………………………………..

Brain Tumors…………………………………………………………..

Hydrocephalus…………………………………………………………

Multiple sclerosis ………………………………………………….

Epilepsies…………………………………………………………………..

Infection of the nervous system……………………………………….

Stupor and Coma………………………………………………

Disorders of upper and lower motor neuron diseases…………….

Dementia………………………………………………………..

Headache……………………………………………

Cauda equina…………………………………

Deficiency Diseases…………………………………

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 Introduction &Anatomy

([Link] Saad)

• Neurology deals with the diagnosis and treatment of all categories

of disease involving the central and peripheral nervous system; or
equivalently, the autonomic nervous system and the somatic
nervous system, including their coverings, blood vessels, and all
effector tissue, such as muscle.
•
• The nervous system is responsible for coordinating all of the body's
activities. It controls not only the maintenance of normal functions
but also the body's ability to cope with emergency situations.

Anatomy of the nervous system

The nervous system is divided into two parts:

1. The central nervous system: consisting of the brain and spinal

cord. These structures are protected by bone and cushioned from
injury by the cerebrospinal fluid (CSF)
2. The peripheral system: which connects the central nervous
system to the rest of the body. The autonomic nervous system
(divided into the sympathetic and parasympathetic nervous
system) is also considered to be a part of the PNS and it
controls the body's many vegetative (non-voluntary) functions.

The Central Nervous system

I) Brain:
The brain is composed of the cerebrum, cerebellum, and
brainstem.

a) The cerebrum is the largest part of the brain and is

composed of right and left hemispheres. It performs higher

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 functions like interpreting touch, vision and hearing, as well
as speech, reasoning, emotions, learning, and fine control of
movement.

• The cerebral hemispheres have distinct fissures, which

divide the brain into lobes. Each hemisphere has 4 lobes:
frontal, temporal, parietal, and occipital.

b) The cerebellum is located under the cerebrum. Its function

is to coordinate muscle movements, maintain posture, and
balance.

c) The brainstem includes the midbrain, pons, and medulla. It

acts as a relay center connecting the cerebrum and
cerebellum to the spinal cord.

• It performs many automatic functions such as breathing,

heart rate, body temperature, wake and sleep cycles,
digestion, sneezing, coughing, vomiting, and swallowing.
• Ten of the twelve cranial nerves originate in the
brainstem.

The surface of the cerebrum has a folded appearance called the

cortex.

The cortex contains about 70% of the 100 billion nerve cells.

The nerve cell bodies forming the cortex named gray matter
and its axons make up the white matter.

Each fold is called a gyrus, and each groove between folds is
called a sulcus.

• Messages within the brain are carried along pathways.

• Messages can travel from one gyrus to another, from one lobe
to another, from one side of the brain to the other, and to
structures found deep in the brain (e.g. thalamus,
hypothalamus).

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Figure 3. The brain is composed of three parts: the brainstem, cerebellum, and
cerebrum.
The cerebrum is divided into four lobes: frontal, parietal, temporal, and occipital.

Deep structures
a) Hypothalamus - is located in the floor of the third ventricle
and is the master control of the autonomic system. It plays a
role in controlling behaviors such as hunger, thirst, sleep,
and sexual response. It also regulates body temperature,
blood pressure, emotions, and secretion of hormones.
b) Pituitary gland - lies in a small pocket of bone at the skull
base called the sella turcica. The pituitary gland is
connected to the hypothalamus of the brain by the pituitary
stalk. Known as the “master gland,” it controls other
endocrine glands in the body.
c) Pineal gland - is located behind the third ventricle. It helps
regulate the body’s internal clock and circadian rhythms by
secreting melatonin. It has some role in sexual
development.
d) Thalamus - serves as a relay station for almost all
information that comes and goes to the cortex. It plays a
role in pain sensation, attention, alertness and memory.
e) Basal ganglia - includes the caudate, putamen and globus
pallidus. These nuclei work with the cerebellum to
coordinate fine motions, such as fingertip movements.

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 f) Limbic system - is the center of our emotions, learning, and
memory. Included in this system are the cingulate gyri,
hypothalamus, amygdala (emotional reactions) and
hippocampus (memory).

Meninges
The brain and spinal cord are covered and protected by three layers
of tissue called meninges. From the outermost layer inward they are:
the dura mater, arachnoid mater, and pia mater.

a) The dura mater is a strong, thick membrane that closely lines

the inside of the skull; its two layers, the periosteal and
meningeal dura, are fused and separate only to form venous
sinuses. The dura creates little folds or compartments. There
are two special dural folds, the falx and the tentorium. The falx
separates the right and left hemispheres of the brain and the
tentorium separates the cerebrum from the cerebellum.

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 b) The arachnoid mater is a thin, web-like membrane that covers
the entire brain. The arachnoid is made of elastic tissue. The
space between the dura and arachnoid membranes is called the
subdural space.
c) The pia mater hugs the surface of the brain following its folds
and grooves. The pia mater has many blood vessels that reach
deep into the brain. The space between the arachnoid and pia
is called the subarachnoid space. It is here where the
cerebrospinal fluid bathes and cushions the brain.

Ventricles and cerebrospinal fluid

• The brain has hollow fluid-filled cavities called ventricles.
• Inside the ventricles is a ribbon-like structure called the
choroid plexus that makes clear colorless cerebrospinal fluid
(CSF).
• CSF flows within and around the brain and spinal cord to help
cushion it from injury.
• This circulating fluid is constantly being absorbed and
replenished.
• There are two ventricles deep within the cerebral hemispheres
called the lateral ventricles.
• They both connect with the third ventricle through a separate
opening called the foramen of Monro.
• The third ventricle connects with the fourth ventricle through
a long narrow tube called the aqueduct of Sylvius.
• From the fourth ventricle, CSF flows into the subarachnoid
space where it bathes and cushions the brain.
• CSF is recycled (or absorbed) by special structures in the
superior sagittal sinus called arachnoid villi.

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 • A balance is maintained between the amount of CSF that is
absorbed and the amount that is produced. A disruption or
blockage in the system can cause a build up of CSF, which can
cause enlargement of the ventricles (hydrocephalus) or cause
a collection of fluid in the spinal cord (syringomyelia).

Figure 7. CSF is produced inside the ventricles deep within the brain. CSF fluid
circulates inside the brain and spinal cord and then outside to the subarachnoid
space. Common sites of obstruction: 1) foramen of Monro, 2) aqueduct of Sylvius,
and 3) obex.

Blood supply
• Arterial Circulation:

- Blood is carried to the brain by two paired arteries, the internal

carotid arteries (anterior cerebral circulation) and the
vertebral arteries (posterior cerebral circulation).
- The internal carotid arteries supply most of the cerebrum.
- The vertebral arteries supply the cerebellum, brainstem, and
the underside of the cerebrum.
- Both “communicate” with each other at the base of the brain
called the Circle of Willis.

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  Anterior cerebral circulation

The anterior cerebral circulation is the blood supply to the

anterior portion of the brain. It is supplied by the following arteries:

1. Internal carotid arteries: These large arteries are the left and
right branches of the common carotid arteries in the neck
which enter the skull, as opposed to the external carotid
branches which supply the facial tissues. The internal carotid
artery branches into the anterior cerebral artery and continues
to form the middle cerebral artery. It also give the ophthalmic
artery and anterior choroidal artery.
2. Anterior cerebral artery (ACA): which has cortical branch
(supplying medial surface of the frontal lobe including
prefrontal cortex, paracentral lobule and medial surface of
motor area for lower limb) and capsular branch (Heubners
artery, supplying the ventral half of the anaterior limb of
internal capsule)
a. Anterior communicating artery: Connects both anterior
cerebral arteries, within and along the floor of the
cerebral vault.
3. Middle cerebral artery (MCA): which has cortical branches
(supplying lateral surface of the frontal lobe and parietal lobe
and anterior part of temporal lobe) and capsular branch
(lenticulostriate artery, supplying the dors hallf of internal
capsule)

 Posterior cerebral circulation

The posterior cerebral circulation is the blood supply to the

posterior portion of the brain, including the occipital lobes,
cerebellum and brainstem. It is supplied by the following arteries:

1. Vertebral arteries: These smaller arteries branch from the

subclavian arteries. Within the cranium the two vertebral
arteries fuse into the basilar artery.
a. Posterior inferior cerebellar artery (PICA)
b. Two spinal arteries which unit forming one anterior
spinal artery.
2. Basilar artery: Supplies the midbrain, cerebellum, and usually
branches into the posterior cerebral artery
a. Anterior inferior cerebellar artery (AICA)
b. Pontine branches
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 c. Superior cerebellar artery (SCA)
3. Posterior cerebral artery (PCA): which has cortical branch
(supplying posterior part of the temporal lobe and whole
occipital) and capsular branch (Thalamogeniculate artery,
supplying the ventral half of the posterior limb of internal
capsule)

4. Posterior communicating artery

Venous Circulation:

- The venous circulation of the brain is very different than the

rest of the body.
- The major vein collectors are integrated into the dura to form
venous sinuses.
- The venous sinuses collect the blood from the brain and pass it
to the internal jugular veins.
- The superior and inferior sagittal sinuses drain the cerebrum,
the cavernous sinuses drains the anterior skull base.
- All sinuses eventually drain to the sigmoid sinuses, which exit
the skull and form the jugular veins.

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 - These two jugular veins are essentially the only drainage of the
brain.

II) Spinal Cord:

General Structure:

 The spinal cord is about 45 cms long, extending from the

medulla down to the second lumbar vertebrae. It acts as a
message pathway between the brain and the rest of the body.
 It is formed of grey matter resembling the letter (H: 2 anterior
and 2 posterior horns) surrounded by white matter (ascending
& desending tracts).
 Formed of 31 segments: 8 cervical, 12 thoracic, 5 lumbar, 5
sacral, 1 coccyx, ends at L1 and continue as Cauda equina
(collection of lumbosacral roots).
 Conus Medullaris: S3, 4,5
 Eiconus: l4, 5, S1, 2

Blood supply:

Three arteries provide blood supply to the spinal cord by running

along its length. These are the two Posterior Spinal Arteries and the
one Anterior Spinal Artery. These travel in the subarachnoid space
and send branches into the spinal cord that communicate with
branches from arteries on the other side.

Function:

The spinal cord is divided into 33 different segments. At every

segment, pair of spinal nerves (right and left) exit the spinal cord and
carry motor (movement) and sensory information.

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These nerves combine to supply strength to various muscles
throughout the body as follows:

C1-C6: Neck flexion

C1-T1: Neck extension
C3-C5: Diaphragm
C5-C6: Shoulder movement and elbow flexion
C6-C8: Elbow and wrist extension
C7-T1: Wrist flexion
C8-T1: Hand movement
T1-T6: Trunk muscles above the waiste
T7-L1: Abdominal muscles
L1-L4: Hip flexion
L2-L4: Thigh adduction
L4-S1: Thigh abduction
L2-L4: Knee extension
L5-S2: Hip extension
L4-S2: Knee flexion
L4-S1: Foot dorsiflexion (move upward) and toe extension
L5-S2: Foot plantar flexion (move downward) and toe flexion

The spinal nerves also provide sensation to the skin in an organized

manner as depicted below.

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Tracts:
Ascending Tracts: Descending tracts
 Dorsal spinocerebral tract  Corticospinal tract
 Ventral spinocerebellar  Rubrospinal tract
tract  Lateral vestibulospinal tract
 Spinocervical thalamic tract  Medial vestibularspinal tract
 Lateral spionothalamic  Reticulospinal tract
tract  Descending autonomic
 Anterior spinothalamic pathway
tract

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Peripheral Nervous System:
• The peripheral system connects the central nervous system to
the rest of the body. The main divisions of the Peripheral
Nervous System are:

a) The autonomic nervous system — which controls the

automatic functions of the body: the heart, smooth
muscle (organs) and glands. It is divided into the “fight-
or-flight” system and the “resting and digesting" system.
b) The somatic nervous system — which allows us to
consciously or voluntarily control our skeletal muscles.

- The somatic system contains 12 cranial nerves and 31

spinal nerves.

Cranial nerves:
• The brain communicates with the body through the spinal cord
and twelve pairs of cranial nerves.
• Ten of the twelve pairs of cranial nerves that control hearing,
eye movement, facial sensations, taste, swallowing and
movement of the face, neck, shoulder and tongue muscles
originate in the brainstem.
• The cranial nerves for smell and vision originate in the
cerebrum.

Function Name Number

Smell Olfactory I
Sight Optic II
moves eye, pupil oculomotor III
moves eye trochlear IV
face sensation trigeminal V
moves eye abducens VI
moves face, salivate Facial VII
hearing, balance vestibulocochlear VIII
taste, swallow glossopharyngeal IX
heart rate, digestion Vagus X
moves head accessory XI

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 moves tongue hypoglossal XII

Functional anatomy:
The brain is made up of two types of cells: nerve cells (neurons) and
glia cells.

a) Nerve cells

• Neurons are comprised of a dendrite, a cell body and an axon.

• Impulses travel to the dendrite into the cell body and then
onto the axon. A special sheath called myelin, which increases
the conductivity of the neuron, covers some nerves.
• As messages travel from one neuron to the next they move
across a synapse.
• At each synapse there is a chemical called a neurotransmitter.
At various parts of the body specific neurotransmitters
facilitate communication, for example dopamine (motor
function), serotonin (mood) and endorphins (painkillers).
• Sensory neurons carry messages from a receptor to the brain.
The brain then interprets the message.
• Motor neurons then send the message to an affector in muscles
and glands.

b) Glia cells

• Glia are the cells of the brain that provide neurons with
nourishment, protection, and structural support. There are
about 10 to 50 times more glia than nerve cells and are the
most common type of cells involved in brain tumors.

• Astroglia or astrocytes transport nutrients to neurons,

hold neurons in place, digest parts of dead neurons, and
regulate the blood brain barrier.

• Oligodendroglia cells provide insulation (myelin) to

neurons.

• Ependymal cells line the ventricles and secrete

cerebrospinal fluid (CSF).

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 • Microglia digest dead neurons and pathogens.

• Physiology of the nervous system:

The nervous system has three general functions: a sensory function,
an interpretative function and a motor function.

1. Sensory nerves gather information from inside the body and

the outside environment. The nerves then carry the
information to central nervous system (CNS).
2. Sensory information brought to the CNS is processed and
interpreted.
3. Motor nerves convey information from the CNS to the muscles
and the glands of the body.

1) Sensory function (Sensory system):

• A sensory system is a part of the nervous system responsible
for processing sensory information. A sensory system consists
of sensory receptors, neural pathways, and parts of the brain
involved in sensory perception.
• Types of sensation:

1- somatic sensations: include

 Superficail sensation: pain, temperature and touch

 Deep sensation: vibration, joint, muscle and nerve sense.
 Cortical sensations: tactile localization, two point
descrimination, perceptual rivalery, stereognosis, and
graphosthesia.

2- Visceral sensation: all sensation from internal viscera.

3- Special sensation: vision, hearing, smell and taste.

• Somatic sensory system:

A somatosensory pathway will typically have three long neurons:
primary, secondary and tertiary (or first, second, and third).

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 • The first neuron always has its cell body in the dorsal root
ganglion of the spinal nerve (if sensation is in parts of the head
or neck not covered by the cervical nerves, it will be the
trigeminal nerve ganglia or the ganglia of other sensory cranial
nerves).
• The second neuron has its cell body either in the spinal cord or
in the brainstem. This neuron's ascending axons will cross
(decussate) to the opposite side either in the spinal cord or in
the brainstem. The axons of many of these neurons terminate
in the thalamus (for example the ventral posterior nucleus,
VPN), others terminate in the reticular system or the
cerebellum.
• In the case of touch and certain types of pain, the third neuron
has its cell body in the VPN of the thalamus and ends in the
postcentral gyrus of the parietal lobe.
• Somatic Sensations has two pathways: posterior column (for
deep sensation and fine touch) and anterolateral system (for
superficial sensation)

Spinal: Anterolateral system Spinal: Dorsal column-

(ALS) medial lemniscal system
Temperature (warm, cold), Fine touch, pressure,
Modalities
pain, itch, crude touch vibration, proprioception
1st order
A-delta & C-fiber A-beta
axon
1st order cell
Dorsal root ganglion Dorsal root ganglion
body
Synapse shortly after entering
1st order path
spinal cord or may ascend few Dorsal columns
in C.N.S.
segments forming lissauer tract
Spinal dorsal horn:
- Substantia gelatinosa of
Medulla, cuneate (from
rolandi (SGR): for pain 2nd order cell
upper body) and gracillis
and temperature body
(from lower body) nuclei
- Main sensory nucleus:
for crude touch
Cross in spinal cord, ascend in
spinoreticular and
anterolateral tracts Cross in medulla, ascend 2nd order
- Lateral spinothalamic: in medial lemniscus axon
for pain and temperature
- Ventral spinothalamic

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 tract for crude touch.
Thalamus VPL (spinothalamic)
3rd order cell
and intralaminar nuclei Thalamus VPL nucleus
body
(spinoreticular)

EFFECTS OF PERIPHERAL AND SPINAL CORD LESIONS

Motor effect of lesion

Sensory effect of Lesion Site of Lesion
(skeletal muscle)
Flaccid paralysis of
muscles innervated by Anesthesia of
nerve (LMN lesion); no peripheral nerves Peripheral nerve
reflex, muscle atrophy, receptive field
fasciculations
Impaired coordination Anesthesia of
Dorsal root or dorsal
due to reduced corresponding
root ganglion
proprioceptive feedback dermatomes
Flaccid paralysis or Ventral root or alpha-
No effect
paresis motoneuron
Spastic paralysis below
the level of the section
Anesthesia below the Total section of the
(UMN lesion); enhanced
level of the section spinal cord
reflex & tone, clonus,
Babinski sign
Hemisection of the
Below the level of the spinal cord (right or left
Below the level of the section, loss of side); note effect of
section, ipsilateral ipsilateral touch- selective lesion in the
paresis or spastic pressure and dorsal quadrant only
paralysis contralateral pain- (sensory effects) or
temperature ventral quadrant only
(motor effects)
Contralateral
Contralateral hemiplegia somatosensory cortex
hemihyposthesia

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II) Interpretative function
(The Cerebral Lobes and cortical areas):
• Each cerebral hemisphere is divided into four lobes; the
frontal, parietal, temporal, and the occipital.

I) The Frontal Lobe is the most anterior lobe of the brain. Its
posterior boundary is the fissure of Rolando, or central sulcus,
which separates it from the parietal lobe. Inferiorly, it is divided
from the temporal lobe by the fissure of Sylvius which is also
called the lateral fissure.

1- Broca's Area (area 44, 45): is found on the inferior third

frontal gyrus in the hemisphere that is dominant for
language. This area is involved in the coordination or
programming of motor movements for the production of
speech sounds. Broca's area is also involved in syntax which
involves the ordering of words, and morphology-the
allomorphs at the ends of words e.g., hat+s=hats. Injuries to
Broca's area may cause apraxia or Broca's aphasia.
2- The precentral gyrus: which may also be called the
primary motor area (area 4)or, most commonly, the motor
strip is immediately anterior to the central sulcus. It controls
the voluntary movements of skeletal muscles; cell bodies of
the pyramidal tract are found on this gyrus.
3- The premotor area or supplemental motor area (area 6):
is immediately anterior to the motor strip. It is responsible
for the programming for motor movements. It does not,
however program the motor commands for speech as these
are generated in Broca's area which is also located in the
frontal lobe.
4- Area for conjugate eye movements (Area 8): is anterior of
the premotor cortex. It facilitates eye movements and is
involved in visual reflexes as well as pupil dilation and
constriction.
5- Areas 9, 10, and 11 are anterior to area 8. They are involved
in cognitive processes like reasoning and judgment which may
be collectively called biological intelligence including
executive function.
6- Paracentral lobule: on the medial surface, concerned with
higher control on micturition centers.

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 7- Prefrontal cortex: the most anterior part of the frontal lobe
is involved in complex cognitive processes like reasoning and
judgment. Also involved in executive function that regulates
and directs cognitive processes, decision making, problem
solving, learning, reasoning and strategic thinking.

II) The Parietal Lobe is immediately posterior to the central sulcus.

It is anterior to the occipital lobe, from which it is not separated by
any natural boundary. Its inferior boundary is the posterior
portion of the lateral fissure which divides it from the temporal
lobe.

The parietal lobe is associated with sensation, including the sense of

touch, kinesthesia, perception of warmth and cold, and of vibration. It
is also involved in writing and in some aspects of reading.

1- The postcentral gyrus which is also called the primary

sensory area (area 1, 2, 3) or the sensory strip is immediately
posterior to the central sulcus. This area receives sensory
feedback from joints and tendons in the body and is organized
in the same manner as the motor strip.
2- Sensory association areas (Areas 5, 7, and 40): are found
posterior to the primary sensory strip and are considered
presensory association areas where somatosensory processing
occurs. These areas are capable of more detailed
discrimination and analysis than is the primary sensory area.
They might, for example, be involved in sensing how hot or
cold something is rather than simply identifying it as hot or
cold.
3- The angular gyrus (area 39): lies near the superior edge of
the temporal lobe, immediately posterior to the supramarginal
gyrus. It is involved in the recognition of visual symbols. Fibers
of many different types travel through the angular gyrus,
including axons associated with hearing, vision, and meaning.
The arcuate fasciculus, the group of fibers connecting Broca's
area in the frontal lobe to Wernicke's area in the temporal lobe
also connects to the angular gyrus. The following disorders
may result from damage to the angular gyrus in the
hemisphere that is dominant for speech and language: anomia,
alexia with agraphia, left-right disorientation, finger agnosia,
and acalcula.

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III) The Temporal Lobe is inferior to the lateral fissure and anterior
to the occipital lobe. It is separated from the occipital lobe by an
imaginary line rather than by any natural boundary.

The temporal lobe is associated with auditory processing and

olfaction. It is also involved in semantics, or word meaning.

1- Wernicke's Area (area): located on the posterior portion of

the superior temporal gyrus in the hemisphere that is
dominant for language. This area plays a critical role in the
ability to understand and produce meaningful speech. A lesion
here will case Wernicke's aphasia.
2- Heschl's Gyrus (area 41) (primary auditory area): is the
area in the temporal where sound first reaches the brain. It is is
also known as the anterior transverse temporal gyrus. There
are two secondary auditory or auditory association areas
(area 42, 21 and 22) which make important contributions to
the comprehension of speech. They are part of Wernicke's
area.
3- Area 42: immediately inferior to area 41 and is also involved in
the detection and recognition of speech. The processing done
in this area of the cortex provides a more detailed analysis than
that done in area 41.
4- Areas 21 and 22 are the auditory association areas.
5- Supramarginal gyrus (Area 37): is found on the posterior-
inferior part of the temporal lobe. Lesions here can cause
anomia.

IV) The Occipital Lobe: which is the most posterior lobe has no
natural boundaries on its lateral aspect. It is involved in vision.

1- The primary visual area (area 17): receives input from the
optic tract via the thalamus.
2- The secondary visual areas (area 18, 19): integrate visual
information, giving meaning to what is seen by relating the
current stimulus to past experiences and knowledge. A lot of
memory is stored here. These areas are superior to the primary
visual cortex.

Damage to the primary visual area causes blind spots in the visual
field, or total blindness, depending on the extent of the injury.
Damage to the secondary visual areas could cause visual agnosia.

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People with this condition can see visual stimuli, but cannot associate
them with any meaning or identify their function.

V) The Insula is a cortical area which lies below the fissure of Sylvius,
it may be involved in programming for speech for speech sounds.

III) Motor function (Motor system):

- Motor system includes:

1- Pyramidal (corticosoinal)tract.
2- Extrapyramidal system.

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 3- Cerebellum.

A. Corticospinal tract (pyramidal)

- From motor cortex to medulla as follow:

 30% from the motor cortex.

 30% from the premotor and supplementary cortex.
 40% from somatosensory areas.

- Divided into:

[Link] (lateral corticospinal tract): 90% of the fibres.

[Link] fibers (anterior corticospinal tract): 10% of the

fibres.

• As corticospinal axons descend from the cortex, they course

through the internal capsule (occupying the the genu and the
anteriot 2/3 of the posterior limb), the cerebral peduncle of the
midbrain, and the ventral pons and onto the ventral surface of
the medulla as the pyramids.
• When corticospinal axons reach the medulla they lie within the
pyramids as corticospinal tract.

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 • At the most caudal pole of the pyramids the corticospinal
axons cross over the midline and now continue their descent
on the contralateral (to the cell of origin) side.
• This crossover point is called the PYRAMIDAL
DECUSSATION.
• The crossing fibers enter the lateral funiculus of the spinal
cord where they are called the LATERAL CORTICOSPINAL
TRACT.
• LCST axons exit the tract to terminate upon neurons in the
spinal cord gray matter along its entire length called anterior
horn cells (AHCs) where its axon form the peripheral nerve
that reach the target muscle.
• All the neurons contributing to the pyramidal and
extrapyramidal systems should be called upper motor
neurons (UMN).
• The anterior horn cells and the related neurons in the motor
nuclei of some cranial nerves are called lower motor neurons
(LMN).

LMNL UMNL Basis of Difference

(STORM Baby)
Lowers Lowers S = Strength
Decreases (flaccid) Increases (spastic) T = Tone
- Fasciculations -Superficial reflexes O = Others
absent
- Fibrillations
-Clonus
- Reaction of
degeneration
Decreased Increased R = Reflexes = DTR or
Deep tendon reflexes
Pathological reflexes
may appear
Decreases / Atrophy Slight loss only M = Muscle Mass
Negative (toe down) Positive (toe up) Baby = Babinski Sign

Muscle tone and reflex:

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Muscle reflex Muscle tone
Induced local axon Spontaneous local axon reflex Nature
reflex
Tapping of muscle Stretch of the muscle (as length Stimulus
tendon of muscle is shorter than
distance between origin and
insertiom)
Golgi tendon Muscle spindle (in the fleshy Receptor
muscle fibers)
The same Excite afferent sensory nerve pathway
to DRG to AHC
Brief muscle Continuous subtetanic (partial) Response
contraction muscle contraction
Muscle nourishment and body Function
posture

Extrapyramidal System
• The pyramidal system was the primary pathway for voluntary
movement.
• The extrapyramidal system is another motor system that is
important for control of movements.
• Neuronal activity for this motor system begins in the cerebral
cortex and ultimately exerts an influence on the lower motor
neurons.
• The pathways are indirect, as opposed to the direct pathways
of the pyramidal system.
• The long axons of the corticospinal tract and corticobulbar
tract make only one synapse with the lower motor neuron, so
the pyramidal system is called monosynaptic.
• The extrapyramidal system, however, is polysynaptic.

The major extrapyramidal nuclei are the basal ganglia.

26

Remember that the basal ganglia is composed of the Globus
Pallidus, Putamen, and Caudate Nucleus.

Together, the Globus Pallidus and Putamen are called the
Lenticular Nucleus.

Together, all three are called the Corpus Striatum.

Other structures related to the extrapyramidal system include
the substantia nigra, red nucleus, subthalamic nucleus, and
reticular formation of the mesencephalon.

The cerebellum is also thought of as contributing to the
extrapyramidal system.

• The extrapyramidal system works by modifying neural

impulses that originate in the cerebral cortex.
• Impulses generated at the primary motor strip are sent via the
extrapyramidal fibers to the basal ganglia.
• In a complex network of pathways, the structures of the basal
ganglia modify impulses and send information to each other.
• Some fibers will then be directed down to synapse with the
lower motor neurons.
• Other fibers are routed through the thalamus and back up to
the cortex.

 The role of the extrapyramidal system includes the following:

 (1) selective activation of movements and supression of others
 (2) Initiation of movements
 (3) setting rate and force of movements
 (4) coordinating movements.

 Damage to the extrapyramidal system, but especially damage

to the basal ganglia, will result in movement disorders known
as dyskinesias. Different types of dyskinesias include:

a) Myoclonus :

- characterized by involuntary single or repetitive jerks of a

body part.
- If the jerks are repetitive, they can be rhythmic or non-
rythmic.
- They can be isolated to one muscle group or a number of
muscles at the same time.
- These movements can occur spontaneously, but also to
stimuli (visual, tactile or auditory).

27
 - Hiccups are a form of myoclonus (brief spasm of
diaphragm.).

b) Tics :

- these are rapid, repeatingly coordinated or patterned

movemetns that are under partial control by the affected
person.
- Often, the person will relate that they have an irresistible
urge to perform the movements.
- They can often supress the movements temporarily.
- Simple tics may appear similar to dystonia or myoclonus.
- Complex tics are coordinated and can involve jumping,
noises, lip smacking, and other rapid, repeated movements.

c) Chorea:

- characterized by rapid, involuntary, random, purposless

movements of a body part.
- Can be present at rest, during sustained postures, and
during movement.
- Can be subtle or obvious.
- These movements can often be modified by the person after
initial onset so that they are made to appear intentional in
order to cover them up.

d) Ballism :

- characterized by gross, abrupt contractions of axial and

proximal muscles of the extremities that can produce flailing.

e) Athetosis :

- A relatively slow, writhing, purposless movement of a body

part.
- Athetosis and choreaic movements often combine with
eachother, and called choreoathetosis.
- Athetosis is a major category of the effects of Cerebal Palsey.

f) Dystonia:

28
 - a slow form of hyperkinesia characterized by involuntary
abnormal postures resulting from excessive co-contraction
of antagonistic muscles.
- Writers cramp is a form of this.

g) Spasm :

- a general term that designates a variety of muscular

contractions. Tonic spasms are prolonged.
- Clonic spasms are repetitive, have a rapid onset, and are
brief.

h) Tremor :

- Rhythmic (periodic) movement of a body part.

- Resting tremors occur when a body part is at rest.
- Postural tremor occurs when the body part is maintained
against gravity.
- Action tremor occurs during movement.
- Terminal tremor occurs as the body part nears a target.
Can be caused by cerebellar circuit problems.

29
 Language And Speech Disorders

([Link] Saad)

Speech is the process of articulation and pronunciation. It

involves the bulbar muscles and the physical ability to form
words.

Language is the process in which thoughts and ideas become
spoken. It involves the selection of words to be spoken, called
semantics, and the formulation of appropriate sentences or
phrases, called syntax.

Definitions
 Dysarthria: is a speech disorder caused by disturbance of
muscular control (articulation of speech).
 Dysphasia: is an impairment of language (formulation of speech).
 Apraxia of speech: is the loss of ability to plan and execute the
oral motor tasks needed in order to speak.
 Inability to write is agraphia if incomplete. Inability to
manipulate numbers is acalculia if incomplete. Difficulty reading
is dyslexia.

• Dysphasia
 Causes:

Dysphasia is impaired ability to understand or use the spoken word.

It is due to a lesion of the dominant hemisphere and may include
impaired ability to read, write and use gestures. The most common
cause is cerebrovascular disease but it can arise from a space-
occupying lesion, head injury or dementia.

Anatomy:

There are several areas of the brain that play a critical role in speech
and language.

1- Broca’s Area

30
Broca’s area, located in the left hemisphere, is associated with speech
production and articulation. Our ability to articulate ideas, as well as
use words accurately in spoken and written language, has been
attributed to this crucial area

2- Wernicke’s Area

This critical language area in the posterior superior temporal lobe

connects to Broca’s area via a neural pathway (Arcuate Fasiculus).
Wernicke's area is primarily involved in the comprehension.
Historically, this area has been associated with language processing,
whether it is written or spoken.

3- Angular Gyrus

The angular gyrus allows us to associate multiple types of language-

related information whether auditory, visual or sensory. It is located
in close proximity to other critical brain regions such as the parietal
lobe which processes tactile sensation, the occipital lobe which is
involved in visual analyses and the temporal lobe which processes
sounds. The angular gyrus allows us to associate a perceived word
with different images, sensations and ideas.

Features of dysphasia

The diagnosis of dysphasia is made only after excluding sensory

impairment of vision or hearing, perceptual impairment (agnosia),
cognitive impairment (memory), impaired movement (apraxia) or
thought disturbance, as in dementia or schizophrenia.

31
Types:
Specific types of dysphasia are associated with damage to particular
cortical regions. Generally, expressive dysphasia suggests an anterior
lesion while receptive dysphasia suggests a posterior lesion. There
are several subtypes. They are:

1- Broca’s (expressive or motor) aphasia:

Due to damage to Broca’s area (area 44) of the language-dominant
hemisphere. People with expressive dysphasia are not fluent and
have difficulty forming words and sentences. There are grammatical
errors and difficulty finding the right word. In severe cases they do
not speak spontaneously but they usually understand what is said to
them.

2- Wernicke’s (receptive or sensory) aphasia:

Due to damage to the posterior superior areas of the language
dominant temporal lobe (often called Wernicke’s area). People with
receptive dysphasia often have language that is fluent with a normal
rhythm and articulation but it is meaningless as they fail to
comprehend what they are saying.

This pattern of receptive aphasia is marked by:

• Fluent, grammatically correct speech with little meaning

• Poor comprehension
• Paraphasic errors:
o calling a spoon a “fork” (semantic)
o calling a spoon a “spood” (literal)
• Neologisms (or nonsense words)

3- Conduction dysphasia/aphasia
Lesions are around the arcuate fasciculus, posterior parietal and
temporal regions. Symptoms are naming deficits, inability to repeat
non-meaningful words and word strings, although there is
apparently normal speech comprehension and production. Patients
are aware of their difficulties.

4- Transcortical sensory dysphasia/aphasia:

32
 Lesions are in the junction areas of the temporal, parietal and
occipital areas of left hemisphere. Symptoms are impaired
comprehension, naming, reading, writing and semantic irrelevancies
in speech.

5- Transcortical motor dysphasia/aphasia:

Lesions are located between Broca's area and supplementary motor
area. Symptoms are transient mutism, telegrammatic, and
dysprosodic speech. Telegrammatic means omitting unimportant
words, as was done when sending a telegram. Dysprosodic speech is
monotone.

6- Global aphasia
If damage encompasses both Wernicke’s and Broca’s areas, global
aphasia can occur. In this case, all aspects of speech and language are
affected. Patients can say a few words at most and understand only a
few words and phrases. They usually cannot carry out commands or
name objects. They cannot read or write or repeat words said to
them.

Dysarthria
Causes of dysarthria

Dysarthria is caused by upper motor neuron lesions of the cerebral

hemispheres or lower motor neuron lesions of the brain stem. It also
results from disruption to the integrated action of upper motor
neurones, basal ganglia and cerebellum.

Types of dysarthria

There may be some variation depending upon the site of the lesion

• Slurred speech: due to upper motor neuron lesion.

• Staccato speech: caused by cerebellar lesions.
• Scanning speech: caused by mixed pyramidal amd cerebellar
lesions.
• Monotonous voice is caused by disease of the extrapyramidal
system in Parkinson's disease..

33
• Nasal tonation: indistinct articulation, hypernasality and
bilateral weakness caused by lower motor neurone disorders
can occur with motor neurone disease.

Urinary System: Normal Anatomy

& Physiology

34
 ([Link] Saad)

 Afferent information on the state of bladder filling is

transmitted from sensory fibers that run in the pelvic nerves to
the sacral dorsal root ganglia, and after transduction of these
signals in the dorsal horn of the spinal cord, this sensory
information is transmitted to the periaqueductal gray (PAG)
matter where it is then relayed via the hypothalamus and
thalamus to the cortical areas (anterior cingulate cortex,
insula, and prefrontal cortex). This allows voluntary control of
micturition by modulating the activity of the PAG, which itself
has excitatory input to the pontine micturition center (PMC).

 The pontine micturition center (PMC) is essential for the co-

ordination of micturition. This is accomplished by the PMC
modulating the opposing effects of the parasympathetic and
sympathetic nervous systems on the lower urinary tract.

 Three mixed sensory and motor nerves (hypogastric, pelvic,

and pudendal nerves) innervate the lower urinary tract.

1- The hypogastric nerve carries sympathetic autonomic

nervous system innervation, it a rises from T11-L2 cord leve l.
Activation of the thoraco-lumbar sympathetic outflow results
in detrusor relaxation and bladder neck (internal s phincter)
contraction.

2- The pelvic nerve carries the parasympathetic autonomic

nervous system innervation. It arises from the detrusor
nucleus at the S2–S4 cord level. Activation of the sacral
parasympathetic outflow results in detrusor contraction and
relaxation of the proximal urethra.

35
 3- The pudendal nerve carries the somatic nervous system
innervation to the lower urinary tract. It arise from the
pudendal (O nuf ’s) nucleus at S2–S4 cord level to supply the
external urethral sphincter striated muscle. Supra-spinal
centers, which normally are under voluntary control, produce
excitatory influence on the pudendal nucleus during the
bladder filling stage to produce external urethral sphincter and
pelvic floor contraction to help maintain continence.

So during the bladder filling stage, supraspinal centers produce

inhibition of the pontine micturition center, which results in
enhancement of thoraco-lumbar sympathetic outflow with
simultaneous suppression of sacral parasympathetic outflow to the
lower urinary tract. These supraspinal centers also produce
excitatory outflow through the pudendal nerve to produce external
urethral sphincter contraction. The overall effect in normal bladder
physiology is detrusor smooth muscle relaxation, bladder neck
smooth muscle and external urinary sphincter skeletal muscle
contraction that allow low pressure storage of urine in the bladder
without leakage. And the opposite occur during the bladder emptying
phase.

36
Pathophysiology of Neurogenic Bladder
Classifications of neurogenic bladder dysfunction:

1- In uninhibited neurogenic bladder dysfunction (Lesion above

the pons):

- Urinary incontinence may occur with brain lesions occurring

above the pontine micturition center, especially with bilateral
lesions.

- Signs of urge incontinence or spastic bladder (termed detrusor

muscle hyperreflexia). Bladder usually empties too quick and
too often with relatively small quantities.

- Usually associated with impotence.

- Since the PMC is intact, the normal opposition of detrusor and

internal/external sphincter tonus is maintained so there are no
high bladder pressures developed that can lead to upper
urinary tract damage. Also no residual volume so no risk of
infection.

2- Spinal cord lesion (Automatic bladder):

- There is urge incontinence like above lesion.

- It is characterized by detrusor-sphincter dyssynergia (DSD),

where in simultaneous detrusor and urinary sphincter
contractions produce high pressures in the bladder (up to 80–
90 cm H2O) leading to vesico-ureteral reflux that can produce
renal damage.

- If detrusor pressure exceeds internal/external urinary

sphincter pressure in the proximal urethra, then incontinence
may occur.

3- Sensory atonic bladder: lesion in the afferent fibres, with

absence sense of fullness of the bladder. The bladder is large and

37
 has low pressure producing urinary retention with overflow
dribbling.

4- Motor atonic bladder: lesion in the pudendal nucleus or nerve.

there is preservation of sense of fullness of the bladder but there
is retention of urine with inability to evacuate the bladder
voluntarily.

5- Sacral cord lesion (Autonomic bladder): In lower motor

neuron neurogenic bladder, the sacral micturition centers or
related peripheral nerves are damaged though the thoracic
sympathetic nervous system outflow to the lower urinary tract is
intact. The bladder capacity is large since detrusor tone is low
(detrusor areflexia) and internal urinary sphincter innervation is
intact. Despite the low detrusor pressure, over flow urinary
incontinence and urinary tract infections are not uncommon.

Vascular Diseases Of The Nervous System

(Cerebrovascular Stroke)

(Dr Mostafa Melek)

38
 Stroke is a major public health problem, being the third most common
cause of death after myocardial infarction and cancer, and the leading
cause of adult disability.

Definition:

• Stroke can be briefly defined as an acute focal neurological

deficit resulting from vascular disease.

• The WHO definition: (Rapidly developing clinical signs of

focal (or global) disturbance of cerebral function, with
symptoms lasting 24 hours or longer, or leading to death, with
no apparent cause other than of vascular origin).

Physiology:
• The adult brain, which weighs about 1500 gm or 2% of the total
body weight, requires an uninterrupted supply of about 150 gm
of glucose and 72 L of oxygen every 24 hours, accounting for
20% of the total body oxygen consumption.
• As the brain does not store these substances, dysfunction results
after only a few minutes of deprivation when either the oxygen
or the glucose content is reduced below critical levels.
• In the resting state, a normal total cerebral blood flow is 50
mL/min per 100 g.

Pathogenesis And Classification:

Brain Infarction

39
 • Brain or neuronal dysfunction occurs at cerebral blood flow levels
of below 50 mg/dL, and irreversible neuronal injury is initiated at
levels below 30 mg/dL.
• When blood supply is completely interrupted for 30 seconds, brain
metabolism is altered.
• After 1 minute, neuronal function may cease. After 5 minutes of
interruption, anoxia initiates a chain of events that may result in
cerebral infarction; however, if oxygenated blood flow is restored
quickly enough, the damage may be reversible, as with a TIA.

Modifiable Risk Factors That May Increase the Probability of Stroke

Modification Risk Factors

Antihypertensives, Diet Hypertension

Antiplatelets Heart disease

Anticoagulants, Antiarrhythmics Atrial fibrillation

Glucose and blood pressure control Diabetes mellitus

Diet, lipid-lowering medication Hypercholesterolemia

Routine exercise Physical inactivity

Cessation Smoking

Quantity reduction Heavy alcohol use

Antiplatelets, endarterectomy, angioplasty Asymptomatic carotid stenosis

Antiplatelets, endarterectomy Transient ischemic attack

Transient Ischemic Attack:

Definition:

40
 Transient ischemic attack (TIA) describes neurologic symptoms of
ischemic origin that last less than 24 hours. In fact, most attacks last only
a few minutes to an hour.
causes:
• When severe major carotid or vertebrobasilar stenosis is present,
transient thrombosis could be operative; such TIAs tend to be brief.
• Attacks without severe stenosis tend to last longer and often are
associated with distal branch occlusion, suggesting embolism from
an ulcerated plaque or a more proximal source.
• Some TIAs, especially vertebrobasilar, may have a hemodynamic
basis, including transient hypotension and cardiac arrhythmia, and
TIAs responsive to calcium-channel blockers suggest a vasospasm
basis.
• Other TIAs may be a consequence of primary, intraparenchymal
vascular disease.
• Fibromuscular dysplasia of the basilar artery and dissection of the
middle cerebral artery.
• TIAs have also been associated with anemia, polycythemia, hyperviscosity,
thrombocythemia, cerebral venous thrombosis, bacterial endocarditis, and temporal
arteritis, and may clear with correction of the underlying disorder.

Signs And Symptoms of TIA:

Symptoms vary with the arterial territory involved.
• Transient monocular blindness (amaurosis fugax): reflecting
ischemia in the territory of the central retinal, consists of blurring
or darkening of vision, peaking within a few seconds (sometimes
as if a curtain had descended), and usually clearing within minutes.

41
 • Limb weakness and
• sensory loss,
• aphasia,
• hemineglect, and
• homonymous hemianopia.
• Posterior circulation TIAs cause symptoms referable to the
cerebrum (visual field loss or cortical blindness), brainstem (cranial
nerve and long tract symptoms, sometimes crossed or bilateral),
and cerebellum.
Recurrent TIAs of the same type are more likely to be the result of
critical narrowing of the involved artery than of embolism.
Diagnosis:
• The differential diagnosis of TIAs includes migraine, cardiac
arrhythmia, seizures, hypoglycemia, compressive neuropathy,
conversion, and neurosis.
• Although TIAs are defined in terms of their clinical reversibility,
and are presumed to signify ischemia too brief or incomplete to
cause infarction, imaging frequently demonstrates appropriately
located infarcts. Some investigators therefore believe that the
definition of TIA should be changed to indicate brief episodes
typically less than one hour without evidence at imaging of acute
infarction.

• Fifteen percent of ischemic strokes are preceded by a TIA.

• After a first TIA, 10% to 20% of patients have a stroke within the
next 90 days, and in half of them, the stroke occurs within the first
48 hours after the TIA.

42
Localization of the Occluded artery

Syndrome Artery Occluded

Asymptomatic Common carotid

Ipsilateral blindness Internal carotid
Contralateral hemiparesis and hemianesthesia
Hemianopia
Aphasia or denial and hemineglect
Middle cerebral
Hemiplegia Main trunk
Hemianesthesia
Hemianopia
Aphasia or denial and hemineglect
Hemiparesis and sensory loss (arm and face more Upper division
affected than leg)
Broca aphasia or denial and hemineglect
Wernicke aphasia or nondominant behavior Lower division
disorder without hemiparesis
Pure motor hemiparesis Penetrating artery
Hemiparesis and sensory loss affect leg more than Anterior cerebral
arm
Impaired responsiveness (abulia or akinetic
mutism‌), especially if bilateral infarction
Left-sided ideomotor apraxia or tactile anomia
Cortical, unilateral: isolated hemianopia (or Posterior cerebral
quadrantic field cut); alexia or color anomia
Cortical, bilateral: cerebral blindness, with or

43
without macular sparing
Thalamic: pure sensory stroke; may leave
anesthesia dolorosa with spontaneous pain
Subthalamic nucleus: hemiballism
Bilateral inferior temporal lobe: amnesia
Midbrain: oculomotor palsy and other eye-
movement abnormalities

Signs That Indicate the Level of Brainstem Vascular Syndromes

Manifestations Structure Artery Affected Syndrome

Medial
Ipsilateral Emerging Paramedian Medulla
Paralysis of gaze to Pontine gaze Paramedian Inferior pons
Ipsilateral abduction Emerging
Internuclear Medial Paramedian Superior

44
 fasciculus

Lateral
syndromes
Dysphagia, Emerging Posterior Medulla
hoarseness, ipsilateral fibers of 9th inferior
paralysis of vocal and 10th cerebellar or
cord; ipsilateral loss nerves vertebral artery
of pharyngeal reflex branches

Vertigo, nystagmus Vestibular

nuclei
Ipsilateral facial Descending
analgesia tract and
nucleus of
fifth nerve
Taste loss on Solitary
ipsilateral half of nucleus and
tongue posteriorly tract
Ipsilateral facial Emerging Anterior Inferior pons
paralysis fibers of inferior
seventh nerve cerebellar
Taste loss on Solitary
ipsilateral half of nucleus and
tongue anteriorly tract
Deafness, tinnitus Cochlear
nuclei

45
Ipsilateral jaw Motor nucleus Mid-pons
weakness of fifth nerve
Ipsilateral facial Emerging
numbness sensory fibers
of fifth nerve

Intracerebral Hemorrhage

Etiologic Factors for Intracerebral Hemorrhage

Demographic
Age
Race/Ethnicity
Vascular Risk Factors
Chronic Hypertension (small vessel disease)
Alcohol
46
Smoking
Low Cholesterol
 Cerebral metastasis
Inflammatory
Vasculitis (cerebral, systemic)
Endocarditis (mycotic aneurysm)
Hematologic
Coagulopathy
Thrombocytopenia
Iatrogenic
Anticoagulants
Fibrinolysis
Toxic
Cocaine
Amphetamines

• Most hemorrhages in the brain parenchyma arise in the region of

the small arteries that serve the basal ganglia, thalamus, and
brainstem and are caused by an arteriopathy of chronic
hypertension or microatheroma.
• Other well established risk factors for intracerebral hemorrhage
include increasing age, cigarette smoking, alcohol consumption,
and low serum cholesterol. Brain tumors, sympathomimetic drugs,
coagulopathies, cavernomas and arteriovenous malformations also
cause brain hemorrhages.
• Because most spontaneous hemorrhages arise from tiny vessels, the
accumulation of a hematoma takes time and explains the smooth
onset of the clinical syndrome over minutes or hours.

47
• Compared with the violence of hemorrhage from aneurysm, terms
like rupture rarely apply.
• The progressive course, frequent vomiting, and headache are major
points that help to differentiate hemorrhage from infarction.
• Hemorrhage usually stops spontaneously by 30 minutes but in fatal
cases, continues until death is caused by brain compression or by
disruption of vital structures.
• The putamen is the site most frequently affected. When the
expanding hematoma involves the adjacent internal capsule, there
is a contralateral hemiparesis, usually with hemianesthesia and
hemianopia and in large hematomas, aphasia or impaired
awareness of the disorder.
• However, small self-limiting hematomas close to the capsular
region may occasionally mimic lacunar syndromes featuring pure
motor or sensory deficits.
• When the hemorrhage arises in the thalamus, hemianesthesia
precedes the hemiparesis.
• Pontine hemorrhage usually plunges the patient into coma with
quadriparesis and grossly disconjugate ocular motility disorders,
although small hemorrhages may mimic syndromes of infarction.
• In the cerebral lobes, white matter hematomas often result from
arteriovenous malformations, amyloid angiopathy, tumors, or other
causes that only uncommonly affect the basal ganglia, thalamus,
and pons.

• Cerebellar hemorrhage warrants separate description because the

mode of onset differs from that of cerebral hemorrhage and
because it often necessitates surgical evacuation.

48
 • The syndrome usually begins abruptly with vomiting and severe
ataxia (which usually prevents standing and walking); it is
occasionally accompanied by dysarthria, adjacent cranial nerve
(mostly sixth and seventh) affection, and paralysis of conjugate
lateral gaze to one side.

Other Cerebrovascular Syndromes

LACUNAR STROKES
• Lacunar strokes are syndromes associated with discrete occlusion
of penetrating arterioles (less than 500 µm diameter), most
frequently due to sustained hypertension and causing cystic
degeneration of brain due to tissue infarction.
• The symptoms depend on the location of the small infarcts, but
may be silent‌with no meaningful symptoms.
• The pathology from sustained hypertension is defined as
lipohyalinosis, although the pathophysiology is uncertain.
• The most common lacunar syndromes are the following:
1. pure motor hemiplegia, usually involving face and limbs on
the side opposite the infarct;
2. pure hemisensory stroke, usually in the same pattern as the
pure motor lacunar stroke;
3. ipsilateral ataxia and hemiparesis; and
4. the dysarthria-clumsy-hand syndrome.

Usually, the prognosis for the lacunar syndrome is good, provided the
expected hypertension is controlled.

HYPERTENSIVE ENCEPHALOPATHY

49
 • This condition, like so-called malignant hypertension, is a medical
emergency requiring immediate hypotensive therapy (rapid acting
agents preferably, such as intravenous labetalol, nicardipine,
sodium nitroprusside, hydralazine, and sometimes angiotensin
converting enzyme (ACE) inhibitors) to minimize serious
neurological complications such as strokes, but care must be made
not to reduce the mean arterial pressure (MAP) below the level of
autoregulation or as an initial mean arterial pressure (MAP)
reduction by 15% to 20%.
• Otherwise, watershed or border-zone infarcts may result because
flow is dependent upon pressure alone.
• patients with hypertensive encephalopathy usually have diastolic
blood pressures of greater than 140 mmHg (except in
toxemia/eclampsia and in children with initial blood pressure
usually much lower than adult men)
• the patients display encephalopathic symptoms such as confusion,
drowsiness, seizures, as well as blurring of vision and headache,
but no focal neurologic signs.
• Fundi frequently show hemorrhages, exudates and disc edema, and
Grade IV Keith-Wagner changes.
• Brain MRI may show posterior leukoencephalopathy with
decreased T1- and increased T2-white matter signal because of
breakthrough which causes diapedesis of serum through the blood
brain barrier. With reduction of MAP, the patient sensorium
frequently clears, a sign that is diagnostic for hypertensive
encephalopathy.

FIBROMUSCULAR HYPERPLASIA

50
 • Fibromuscular bands of uncertain etiology form segmental
narrowing of large arteries such as the carotid artery, and the
bands may provoke platelet adhesion and thereby cause transient
ischemic attacks or infrequently thromboembolic strokes.
• Most frequently they present with asymptomatic carotid bruits or
are seen incidentally, during a cerebral angiogram and has the
appearance of a string of pearls.
• If the renal artery is involved, patients may develop hypertension;
bruits may be heard over the renal artery.
• Antiplatelet drugs, anticoagulation, and angioplasty have been
reported to reduce the frequency of TIAs in patients presenting
with them.
Stroke in Young Adults, causes:

51
 • CADASIL: Cerebral Autosomal Dominant Arteriopathy with
Subcortical Infarcts and Leukoencephalopathy
• Dissection (traumatic or spontaneous)
• Fibromuscular Dysplasia
• Migraine
• MELAS, mitochondrial encephalopathy with lactic acidosis and
stroke-like events
• Moyamoya syndrome
• Oral contraceptive use, including low-dose estradiol pills
• Venous occlusive diseases

Cardiogenic emboli

• Anatomic abnormalities and atherosclerosis patent foramen ovale

(PFO); mitral valve prolapse, with redundancy of the mitral leaflet;
valvular replacement; & cardiomyopathies post-myocardial
infarction, and alcoholic; endocardial fibrosis; aortic atheromas
without)
• Arrhythmias (especially atrial fibrillation and sick-sinus syndrome)
• Immunecomplex disorders and paraneoplastic syndromes
(Libman-Sacks Syndrome with systemic lupus erythematosus;
nonbacterial thrombotic endocarditis or marantic endocarditis, seen
in AIDS and with neoplasms, occult and otherwise)
• Infections (bacterial endocarditis; viral cardiomyopathy; rheumatic
heart disease
• Tumors (atrial myxoma)

Blood elements

52
 • Erythrocytes (sickle cell disease; polycythemia vera)
• Platelets (thrombocytosis, usually >1 million/cmm; thrombotic
thrombocytopenia purpura)
• Proteins (resistance to protein C activation, Factor V-Leiden;
antiphospholipid syndrome, Sneddon syndrome; Waldenstrom
macroglobulinemia)
• Coagulation defects (deficiency of protein C, S and Antithrombin
III, alcohol-induced prothrombotic state; paroxysmal nocturnal
hemoglobinuria; plasminogen-activator inhibitor-1, PAI-1
polymorphism; prothrombin polymorphism)

Treatment and Prevention of Strokes

• Therapies for stroke management and prevention are designed

to: (1) minimize or prevent stroke occurrence, (2) optimize
functional recovery following strokes, and (3) avert stroke
recurrences. Specific measures for treatment and prevention
depend upon the stroke syndrome being considered.
• Stroke syndromes are conveniently divided by neuroimaging
findings and are classified as either ischemic or hemorrhagic.
• With ischemic strokes, the primary causes are atherothrombotic,
with artery-to-artery thromboembolism and cardioembolic
strokes with other causes from prothrombotic conditions noted
above.
• Treatment and prevention will be directed primarily to
atherothrombotic brain infarction (ABI) and cardioembolic
strokes.

53
 • Hemorrhagic strokes are categorized as: subarachnoid
hemorrhages, primarily arising from berry or congenital
aneurysms but may also be the result of a variety of
arteriovenous malformations; and intracerebral hemorrhage,
most commonly caused by sustained hypertension, but may
occur with hypocoagulable states as well as either primary or
metastatic tumors in the brain

ATHEROTHROMBOTIC STROKES AND TIAS

• ABI, usually with artery-to-artery thromboembolism, is the most

common stroke syndrome; it results from atherosclerotic lesions that
are primarily extracranial in white populations, while primarily
intracranial in African American and Asian people.
• The syndromes of ABI form a continuum from TIAs to completed
infarction with fixed neurologic deficits.
• Whether an intermediate condition of stroke-in-evolution or
progressing stroke exists is controversial.
• Thrombosis on an atherosclerotic plaque may occur for several
pathologic reasons. The first of these, and most common, is rupture
of the plaque that stems from a high concentration of cholesterol-
esters, foam cells, and inflammatory constituents that make the
plaque unstable.
• For TIAs caused by carotid stenosis of equal to or greater than 70%
by diameter, carotid endarterectomy (CEA) by a skilled surgeon
with an acceptable track record is the treatment of choice over
medical therapy, in good surgical candidates.
• Efforts to determine the value of angioplasty and stents is being

54
 investigated, both for extra- and intracranial stenosis.
• To prevent TIA recurrence and the potentials for a completed
stroke in subjects with TIAs or minor strokes caused by extra- or
intracranial occlusive disease, antiplatelet drugs such as aspirin
have been effective.

• Studies on the benefits of aspirin show a reduction of strokes

by approximately 25%.
• The optimum dose of daily aspirin, whether ultra-low doses at
30 to 75 or 80 mg to high doses of 1,300 mg remains
controversial, but low doses appear effective and have less side
effects such as gastrointestinal bleeding.
• The action of aspirin is to acetylate irreversibly and inhibit
platelets cyclooxygenase I, which thereby stops synthesis of the
powerful platelet aggregant thromboxane A2 (TXA2).
• Lower doses of aspirin have the advantage of minimizing
inhibition of endothelial cells production of prostacyclin (PGI2),
the powerful platelet antiaggregant.
• Newer anti-platelet drugs, which blunt the GP IIbIIIa receptor
which is involved in platelet adhesion, appear to operate
synergistically with aspirin in potentiating aspirin anti-aggregant
effects; these drugs are ticlopidine and clopidogrel and
dipyridamole in combination with aspirin. Clopidogrel, an
analog of ticlopidine, has fewer side effects such as diarrhea,
bruising and leucopenia which require frequent monitoring
when using ticlopidine.
• Dipyridamole plus aspirin may be the best combination to

55
 reduced recurrent TIAs or ischemic strokes following TIAs.
• Aspirin and clopidogrel increases bleeding so this combination
should be avoided for chronic therapy.

COMPLETED STROKES WITH FIXED NEUROLOGIC DEFICITS

• For patients with ischemic strokes caused by ABI or cardiogenic

emboli, who had a negative CT or MRI of brain for bleeding and
minimal infarction, and who were seen within 3 hours of onset of
symptoms, the thrombolytic agent, tissue plasminogen activator
(tPA), was found beneficial. tPA was approved for patient use by
the FDA in 1996.
Tissue Plasminogen Activator (tPA) Exclusion Criteria

Stroke or head trauma within the preceding 3 mths

Major surgery within the preceding 2 wks
History of intracerebral hemorrhage

56
Blood glucose >400 mg/dL (21.6 mmol/L)
Patients requiring very aggressive therapy attempts for blood pressure
reduction

EMBOLIC STROKES OF CARDIAC AND AORTIC ORIGIN

• Treatment of cardiogenic emboli depends on the offending
pathology: -- infected prosthetic valves need replacement, and
myxomatous emboli require surgical removal of the tumor.
• The most common cause of cardiogenic emboli (more than 50% of
cases) is from arrhythmias, particularly atrial fibrillation, with or
without mitral pathology, and recent myocardial infarction (MI).
• Post-MI emboli occur with large, anterior or septal infarcts,
particularly those with akinetic segments, as detected by 2D
echocardiography.
• Mitral valve prolapse and patent foramen ovale (PFO), both
discussed above, occur more commonly in young adults.
• In embolic strokes caused by atrial fibrillation, anticoagulation to
reduce embolization is indicated with an international normalized
ratio (INR) between 2.0 and 3.0.
• In the Stroke Prevention in Atrial Fibrillation (SPAF) study,
anticoagulation reduced stroke recurrence substantially, even in
patients over the age of 75 years.
• Chances of embolization are associated with the following risk
factors: previous embolization, left ventricular hypertrophy with
reduced ejection fraction, sustained hypertension, and congestive
failure.

57
 • Aortic atheromas measuring at least 4 mm or more, without
calcification, are considered thrombogenic, and anticoagulation to
prevent embolization is being investigated for these patients.

INTRACEREBRAL HEMORRHAGE

• Acute treatment of intracerebral hemorrhage includes airway

protection, adequate ventilation, and blood pressure levels below a
mean arterial pressure of 130 mmHg.
• Fluid balance and body temperature should be maintained at normal
levels. Increased intracranial pressure may require osmotherapy,
controlled hyperventilation, or barbiturate-induced coma.
• The administration of corticosteroids is generally avoided.
• Apart from cases suffering cerebellar hemorrhage, any decision on
whether, how, and when to intervene neurosurgically after
intracerebral hemorrhage is subject to current debates and awaits
data from ongoing prospective trials.
• To date all clinical trial attempts have failed to show a superiority of
hematoma evacuation over medical therapy, save for cerebellar
hemorrhage, where surgery for the larger masses may be lifesaving
and may be followed by satisfactory clinical outcomes

SUBARACHNOID HEMORRHAGE (SAH)

• Extirpation of the aneurysm is the definitive therapy for aneurysms

causing SAH and may be accomplished surgically or with balloons
and coagulation techniques, such as with coils deposited in the
aneurysm.

58
 • Following SAH and prior to surgery, patients should be sedated and
kept in a quiet environment to prevent elevations of blood pressure
that may provoke rebleeding, which is a major complication of
SAH, along with vasospasm, ventricular dilatation, and Syndromes
of Inappropriate ADH Secretions (SIADH).
• Antifibrinolytic agents, such as epsilon-amino-caproic acid, used to
preserve the thrombus around an aneurysm thereby preventing
rebleeding, have been unsuccessful.
• Vasospasm may be minimized with the calcium channel antagonist,
nimodipine, which crosses the blood-brain barrier; intrathecal
thrombolytic therapy may be useful in reducing vasospasm.
Hydrocephalus may require ventricular shunting.
• Assessment of nitric oxide synthase (eNOS) polymorphism may be
of value in predicting whether or not asymptomatic aneurysms are
more likely to bleed.

STROKE REHABILITATION

• A team approach for stroke rehabilitation, starting from a stroke

recovery unit with experienced physiatrists and physical therapists,
has proven beneficial for the optimum recovery of patients
• . This approach is particularly helpful in averting various
complications from strokes, such as infections, contractures, and
decubiti, and in maximizing independence for patients with
hemiplegia/paresis by teaching them to transfer effectively from bed
to wheelchair.
• Activities of daily living (ADLs) may be optimized for personal
hygiene, dressing, and feeding, as well.

59
 • Depression is a frequent accompaniment of strokes, partially
because the reality of a physical disability exists but also because
there is altered brain chemistry, which may respond well to selective
serotonin-reuptake inhibitors (SSRIs) and tricyclic antidepressants.
• Speech and occupational therapists should be consulted to help
patients improve their communication skills and ADL skills.

STROKE PREVENTION
• Stroke prevention depends upon the stroke syndrome and its
pathology, such as atherosclerosis, arteritis, cardiac diseases,
dissection, and so on, but since atherosclerosis is the most common
cause of ischemic strokes, the primary stroke syndrome, only
interventions to prevent atherosclerosis will be reviewed here.

• The risk factors for atherosclerosis are well known and require the
active involvement of the physician to help patients develop
motivational drives to control or stop these risk factors, which
include hypertension, smoking, diabetes mellitus, elevated
cholesterol, or more correctly, increased low-density lipoprotein
(LDL), obesity, sedentary life, and negative stress levels.

60
 Multiple Sclerosis & Other
Inflammatory Demyelinating
Diseases of the Central Nervous
System

([Link] Alahmar)

• Neurological Diseases with relative preservation of axons, loss of

oligodendrocytes, and astroglial scarring.
• Certain clinical features are typical of MS, but the disease has a
highly variable pace and many atypical forms.
• Investigative studies are often needed to confirm the diagnosis and
exclude other possibilities.
• Advances in disease monitoring and treatment hold promise of
slowing the progression of disability.
• Understanding of the basic nature of the disease remains limited, and
better control of the disease and repair of damaged CNS tissue
remain as goals for the near and more distant future.

Diseases of Myelin
• AUTOIMMUNE
o Acute disseminated encephalomyelitis
o Acute hemorrhagic leukoencephalopathy
o Multiple sclerosis
• INFECTIOUS
o Progressive multifocal leukoencephalopathy
• TOXIC/METABOLIC
o Carbon monoxide
o Vitamin B12 deficiency
o Mercury intoxication (Minamata disease)
o Alcohol/tobacco amblyopia
o Central pontine myelinolysis
o Marchiafava-Bignami syndrome
o Hypoxia
o Radiation
o VASCULAR
o Binswanger’s disease
• HEREDITARY DISORDERS OF MYELIN METABOLISM
o Adrenoleukodystrophy
o Metachromatic leukodystrophy
o Krabbe’s disease

61
 o Alexander’s disease
o Canavan-van Bogaert-Bertrand disease
o Pelizaeus-Merzbacher disease
o Phenylketonuria

PATHOLOGY

The pathological hallmark of MS is the cerebral or spinal plaque,
which consists of a discrete region of demyelination with relative
preservation of axons, although spectroscopic and pathological
studies suggest some axonal loss may be an integral part of the
disease process.

Gross examination of the brain in MS often reveals variable degrees
of atrophy and ventricular dilatation.

Plaques may be visible on the surface of the spinal cord on
inspection.

The cut surface of the brain reveals the plaques, which, when active,
appear whitish yellow or pink, with somewhat indistinct borders.

Older plaques appear translucent with a blue-gray discoloration and
sharply demarcated margins.

These plaques often have a hard or rubbery consistency.

Individual lesions are generally small (1 to 2 cm), but may become
confluent, generating large plaques.

Plaques develop in a perivenular distribution and are seen most
frequently in the periventricular white matter, brainstem, and spinal
cord.

However, large numbers of small plaques, often detected only by
microscopy, are found in cortical regions affecting intracortical
myelinated fibers.

One of the earliest features of acute MS lesions is a disruption of
the blood-brain barrier (BBB) as detected by MRI

ETIOLOGY:
a) Autoimmunity
• Low levels of autoreactive T cells and B cells are present in
normal individuals.

62
• Presumably they have escaped from clonal deletion during
the process of immune development and are now tolerant of
their antigens.
• Autoimmunity develops when these cells lose tolerance and
a complex process of immune reactivity in target tissues
begins.
• One potential way in which tolerance can be broken is by
means of molecular mimicry between self-antigens and
foreign antigens; for example, viral components.
• Several viral and bacterial peptides share structural
similarities with important proteins of myelin, and a few of
them are able to activate specific T-cell clones derived from
patients with MS.
• Another way in which tolerance can be broken is by CNS
infection, causing tissue damage and releasing antigens into
the peripheral circulation, where they may encounter
corresponding autoreactive T cells.
• Myelin basic protein (MBP) has long been considered one of
the primary candidates for an autoimmune attack.
• T cells that respond to MBP are found in the peripheral
blood in normal and in those with MS, possibly at higher
levels in patients with MS with active disease.
• MBP, which accounts for 30% of the protein of myelin, can
be an antigen for EAE, the primary animal model of MS.
• Recent clinical trials with altered peptide ligands of MBP
support the potential pathogenic role of MBP-reactive T
cells.

63
 • Several other proteins characteristic of myelin are also
candidates for an autoimmune attack.
• Proteolipid protein accounts for 50% of CNS myelin protein
and is an integral membrane protein of the myelin leaflets.
• In the PNS, P0 protein fulfils this role.
• Myelin-associated glycoprotein, myelin oligodendrocyte
glycoprotein, and cyclic nucleotide phosphodiesterase are
proteins that account for a few percent of myelin.
• Myelin oligodendrocyte glycoprotein and cyclic nucleotide
phosphodiesterase are not found in peripheral nerve myelin
and are, therefore, of interest because MS is a disease
affecting only central myelin.
• Although the possibility of autoimmunity as the causal
mechanism for MS exists, the issue is not proven.
• The actual target antigen and the details of the
immunopathological process are not yet fully understood.
• The evidence for MS being a dysimmune condition is more
compelling; with alterations in immune cell repertoire and
activation state both in blood andCSF of MS patients
compared to others.
b) Infection
• A possible role for microbial infection in the causation of MS
has been a matter of ongoing debate for decades.
• More recently, human herpesvirus-6 (HHV-6), Epstein-Barr
virus (EBV), and Chlamydia pneumoniae have been the focus of
interest as potential triggers for MS.
• Several studies of serum and CSF samples have yielded varying
results. For example, one early study showed 47% of MS brains

64
 were positive for HHV-6, and 80% showed elevation of
antibodies in the serum.
• A more recent study found no HHV-6 DNA in any CSF sample,
and the serum antibody titers were comparable to the general
population.
• As has been stated before, the final word about viruses or other
microbes and MS is pending.

EPIDEMIOLOGY
a) Age of Onset
• Most studies agree that the mean and median age of onset
inrelapsing forms of MS is age 29 to 32.
• The peak age of onset is approximately 5 years earlier for
women than for men. Primary progressive MS has a mean age of
onset of 35 to 39 years.

b) Sex Distribution
• Autoimmune diseases in general and MS in particular affect more
women than men.
• In a summary of 30 incidence and prevalence studies, a cumulative
ratio of female to male subjects was 1.77 to 1.00.
c) Geographical and Racial Distribution
• High-frequency areas of the world, with current prevalence of 30
per 100,000 or more, include all of Europe (including Russia),
southern Canada, the northern United States, New Zealand, and the
southeastern portion of Australia.
• Medium frequency areas with prevalence of 5-25 per 100,000
comprise most of Australia, the southern United States, the
Mediterranean basin (other than Italy), the Asian parts of the
former Soviet Union, parts of South America, and the white
population of South Africa.
• Low-risk areas with prevalence of less than 5 per 100,000 include
most of South America, Mexico, most of Asia, and all of Africa.
One possible conclusion is that MS is a location-related illness,
with a latitude gradient.
d) Genetics

65
 • The frequency of familial occurrence of MS has varied from 3% to
23% in different studies.
• An overall risk in first degree relatives of 5% seems a reasonable
estimate. The risk is highest for siblings and decreases
progressively for children, aunts, uncles, and cousins.
• For genetic counseling purposes, the sibling risk is 3% to 5%,
approximately 30 to 50 times the background risk for this same
population. In some studies unaffected family members may have
been found to have abnormalities on MRI, implying that the risk
may be even higher.
• Several candidate genes for MS have been identified, including
those coding for human leukocyte antigen (HLA), T-cell receptor,
MBP, portions of the immunoglobulin chain, and mitochondrial
genes.
• Three entire genomic scans for MS susceptibility genes have been
reported, without an identifiable region of major interest beyond
the HLA complex region of chromosome 6.
• The data argue for non- Mendelian polygenic inheritance.

CLINICAL SYMPTOMS AND PHYSICAL

FINDINGS
• Although the clinical syndrome of MS is classically described as a
relapsing-remitting disorder that affects multiple white matter
tracts within the CNS, with usual onset in young adults, the
disorder displays marked clinical heterogeneity.
• This variability includes age of onset, mode of initial
manifestation, frequency, severity and sequelae of relapses, extent
of progression, and cumulative deficit over time.
• The varied clinical features reflect the multifocal areas of CNS
(primarily myelin) destruction (MS plaques), although
discrepancies occur between the extent of clinical and pathological
findings.
• The high degree of variability and the difficulty in predicting the
course and severity make MS one of the most puzzling of CNS
diseases.
• The symptoms and signs of MS primarily reflect conduction block
from large demyelinated segments or axonal damage as well as
conduction delay through smaller demyelinated segments, which
produce critical temporal dispersion.
1) Cognitive Impairment

66
 • Data from formal neuropsychological studies indicates that
cognitive involvement has been underreported in MS.
• Neuropsychological test results have shown that 34% to 65% of
patients with MS have cognitive impairment.
• The most frequent abnormalities are with abstract
conceptualization, recent memory, attention, and speed of
information processing.
• Patients complain of memory loss or frustration.
• The abnormalities are usually not apparent during a routine office
visit.
• The cognitive deficit of the MS patient is most obvious when he or
she confronts multiple stimuli in a pressured environment.
2) Affective Disorders
• Depression is the most common manifestationand is in part
secondary to the burden of having to cope with a chronic, incurable
disease.
• However, it is more prevalent in MS than in other chronic diseases,
suggesting an organic component as well.

• The lifetime risk of major depression in patients with MS is up to

50%, compared with 12.9% in patients with chronic medical
conditions in another study.

• Some data indicate a comorbid association, presumably genetic,

between bipolar illness and MS. Suicide rates are higher in patients
with MS than in the general population or when compared to
patients with other chronic illnesses.
• Frontal or subcortical white matter disease may also be a
contributory causative factor.
• Euphoria, formerly considered to be common in MS, is actually
infrequent and is usually associated with moderate or severe
cognitive impairment and greater disease burden on MRI.
• Patients may manifest a dysphoric state with swings from
depression to elation.
3) Cranial Nerve Dysfunction
i. Impairment of the Visual Pathways
• Optic neuritis (ON) is the most frequent type of involvement of the
visual pathways, usually presenting as an acute or subacute
unilateral syndrome characterized by pain in the eye accentuated

67
 by ocular movements, which is followed by a variable degree of
visual loss affecting mainly central vision.
• Recurrence is highly variable.
• Mapping of visual fields reveals a central or cecocentral scotoma
(central scotoma involving the physiological blind spot).
• The lesion of the optic nerve is retrobulbar, and funduscopic
examination is normal in the acute stage.
• Later the optic disc becomes pale as a result of axonal loss. This
pallor predominates in the temporal segment of the disc (temporal
pallor).
• After an attack of acute ON, 90% of patients regain normal vision,
typically over a period of 2 to 6 months.
• Desaturation of bright colors, particularly red, is often reported by
recovered patients; some also report a mild nonspecific dimming of
vision in the affected eye.
• Uhthoff’s phenomenon refers to a decrease in visual acuity following an
increase in body temperature. This can occur after exercise, a hot bath, or
fever. This phenomenon, which reflects subclinical demyelination or
preexistent injury to the optic nerve, may occur without a history of clinical
involvement of the optic nerve. A similar phenomenon can occur at other
sites of CNS damage with an increase in body [Link] basis for
this phenomenon is an alteration in conduction efficiency when body
temperature rises such that subclinical conduction defects become clinically
apparent.

ii. Impairment of the Ocular Motor Pathways

• Impairment of individual ocular motor nerves is infrequent in MS.
• When present, the involved nerves are, in decreasing order of
frequency, cranial nerves VI, III and, rarely, IV.
• More frequent findings are those that reflect lesions of vestibulo-
ocular connections and internuclear connections.

Internuclear ophthalmoplegia, defined as abnormal horizontal ocular

movements with lost or impaired adduction and horizontal nystagmus of the
abducting eye, is secondary to a lesion of the medial longitudinal fasciculus on the
side of diminished adduction.

iii. Impairment of Other Cranial Nerves

• Impairment of facial sensation, subjective or objective, is a
relatively common finding in MS.
• The occurrence of trigeminal neuralgia in a young adult is
frequently an early sign of MS.

68
• Facial myokymia, a fine undulating wavelike facial twitching, and
hemifacial spasm can be caused by MS, but other causes of a focal
brainstem lesion must be excluded.
• Unilateral facial paresis can occur, but taste sensation is almost
never affected. In these syndromes, as with acute oculomotor
palsy, the nerve is affected in its course within the brainstem, rather
than peripherally.
• Vertigo is a reported symptom in 30% to 50% of patients with MS
and is commonly associated with dysfunction of adjacent
brainstem or cranial nerves.
• Resulting associated symptoms include hyperacusis or hypoacusis,
facial numbness, and diplopia.
• Complete hearing loss, usually unilateral, is an infrequent
complaint.
• Malfunction of the lower cranial nerves is usually of the upper
motor neuron type (pseudobulbar syndrome) and is usually a rather
late finding in MS.
4) Impairment of the Sensory Pathways
• Sensory manifestations are a frequent initial feature of MS and are
present in almost every patient at some time during the course of
disease.
• The sensory features can reflect spinothalamic, posterior column,
or dorsal root entry zone lesions.
• The sensory symptoms are commonly described as numbness,
tingling, pins and needles, tightness, coldness, itching, or swelling
of limbs or trunk.
• Radicular pains, unilateral or bilateral, can be present, particularly
in the low thoracic and abdominal regions, or a bandlike abdominal
sensation may be described.
• The most frequent sensory abnormalities on clinical examination
are varying degrees of impairment of vibration and joint position
sense, decrease of pain and light touch in a distal distribution in the
four extremities, and patchy areas of reduced pain and light touch
perception in the limbs and trunk.
5) Impairment of the Motor Pathways
• Corticospinal tract dysfunction is common in MS.
• Paraparesis, or paraplegia, occurs more frequently than significant
weakness in the upper extremities.
• With severe spasticity, extensor or flexor spasms of the legs and
sometimes the trunk may be provoked by active or passive
attempts to rise from a bed or wheelchair.

69
• The physical findings include spasticity, usually more marked in
the legs than in the arms.
• The deep tendon reflexes are exaggerated, sustained clonus may
be elicited, and extensor plantar responses are observed.
• All of these manifestations are commonly asymmetrical.
6) Impairment of Cerebellar Pathways
• Cerebellar pathway impairment results in gait imbalance, difficulty
in performing coordinated actions with the arms, and slurred
speech.
• Examination reveals the usual features of cerebellar dysfunction,
such as dysmetria, decomposition of complex movements, and
hypotonia, most often observed in the upper extremities.
• An intention tremor in the limbs and titubation of the head may be
seen, Walking is impaired by ataxia.
• Ocular findings of nystagmus, ocular dysmetria, and frequent
refixation saccades suggest cerebellar or cerebellovestibular
connection dysfunction. Speech can be scanning or explosive in
character.
7) Impairment of Bladder, Bowel, and SexualFunctions
• The extent of sphincter and sexual dysfunction often parallels the
degree of motor impairment in the lower extremities.
• The most common complaint related to urinary bladder
dysfunction is urgency, usually the result of uninhibited detrusor
contraction, reflecting a suprasegmental lesion.

• Constipation is more common than fecal incontinence and is

mainly due to decreased general mobility and the tendency of MS
patients to restrict their fluid intake in a misguided attempt to
decrease urinary urgency and incontinence. Almost all patients
with paraplegia require special measures to maintain regular bowel
movements.
• Sexual dysfunction, although frequently overlooked, occurs
commonly in MS. Approximately 50% of patients become
completely sexually inactive secondary to their disease, and an
additional 20% become sexually less active.
• Men experience various degrees of erectile dysfunction, often with
rapid loss of erection at attempted intercourse.
• Most women preserve their orgasmic capabilities, sometimes even
in the presence of complete loss of bladder and bowel function.

70
• CLINICAL FEATURES SUGGESTIVE OFMS CLINICAL FEATURES NOT SUGGESTIVE OF
MS
• Onset between ages 15 and 50 Onset before age 10 or after age 60
• Involvement of multiple areas of the CNS involvement of the PNS
• Optic neuritis Hemianopsias
• Lhermitte’s sign Rigidity, sustained dystonia
• Internuclear ophthalmoplegia Cortical deficits such as aphasia,apraxia,alexia, neglect
• Fatigue Deficit developing within minutes
• Worsening with elevated body temperature Early dementia

DIAGNOSTIC CRITERIA
• More recently, McDonald and colleagues proposed new diagnostic
criteria that include detailed guidelines for MRI and timing
intervals to determine possible or definite MS.

Paraclinical Evidence in MS Diagnosis:
• WHAT IS A POSITIVE MRI?
Three out of four of the following:
• 1 gadolinium-enhancing brain or cord lesion or 9 T2
hyperintense brain and/or cord lesions if there is no
gadolinium- enhancing lesion
• 1 or more brain infratentorial or cord lesions
• 1 or more juxtacortical lesions
• 3 or more periventricular lesions
Note: Individual cord lesions can contribute along with individual brain lesions to reach required

number of T2 lesions.

• WHAT PROVIDES MRI EVIDENCE OF DISSEMINATION IN

TIME?
A gadolinium-enhancing lesion detected in scan at least 3
months after onset of initial clinical event at a site different
from initial event - or -

71
 A new T2 lesion detected in a scan done at any time
compared to a reference scan done at least 30 days after
initial clinical event
• WHAT IS POSITIVE CSF?
Oligoclonal IgG bands in CSF (and not serum) or elevated
IgG index
• WHAT IS POSITIVE VEP?
Delayed but well-preserved waveform

Differential Diagnosis in Multiple Sclerosis

INFLAMMATORY DISEASES
Granulomatous angiitis
Systemic lupus erythematosus
Sjögren’s disease
Behçet’s disease
Polyarteritis nodosa
Paraneoplastic encephalomyelopathies
Acute disseminated encephalomyelitis, postinfectious
encephalomyelitis
INFECTIOUS DISEASES
Lyme neuroborreliosis
Human T-cell lymphotropic virus type 1 infection*
Human immunodeficiency virus infection
Progressive multifocal leukoencephalopathy*
Neurosyphilis*
GRANULOMATOUS DISEASES
Sarcoidosis
Wegener’s granulomatosis
Lymphomatoid granulomatosis
DISEASES OF MYELIN
Metachromatic leukodystrophy (juvenile and adult)*
Adrenomyeloleukodystrophy*
MISCELLANEOUS
Spinocerebellar disorders*
Arnold-Chiari malformation
Vitamin B12 deficiency*
*Indicates disorders that are predominantly important to
differentiate in the setting of progressive disease.

72

Revised McDonald et al. (2005) Diagnostic Criteria for Multiple Sclerosis

CLINICAL (ATTACKS) OBJECTIVE LESIONS ADDITIONAL REQUIREMENTS TO MAKE DIAGNOSIS

2 or more 2 or more None. Clinical evidence alone will suffice; additional evidence
desirable but must be consistent with MS

2 or more 1 Dissemination in space by MRI or 2 or more MRI lesions

consistent with MS plus positive CSF or await further clinical attack implicating other site

1 2 or more Dissemination in time by MRI or second clinical attack

1 1 Dissemination in space by MRI or 2 or more MRI lesions

consistent with MS plus positive CSF AND dissemination in time by MRI or second clinical attack

0 (progression from onset) 1 or more Disease progression for 1 year (retrospective or prospective)
AND 2 out of 3 of the following:
Positive brain MRI (9 T2 lesions or 4 or more T2 lesions with positive VEP)
Positive spinal cord MRI (2 or more focal T2 lesions)
Positive CSF

Effect of Exogenous Factors on the Course

• A disproportionately high number of relapses occur in patients with
MS who have suffered recently from viral infections, and a high
number of infections are followed by acute attacks.
• Increased interferon- g and TNF-a produced by cells of the
immune system during viral infections may play a role in this
increased relapse rate by increasing expression of major
histocompatibility complex class II antigens and adhesion
molecules on cells of the immune system and CNS, with a resultant
increase in the number of activated T cells being attracted to the
CNS.
• Controversy exists about a link between occurrence of stressful
events and exacerbation of MS.
• Trauma appears not to be implicated in disease induction or
relapse. Performance of neurological diagnostic procedures such as
myelography and lumbar puncture has not been linked with

73
 aggravation of the MS disease course, nor has administration of
local or general anesthetics or surgery.
• Recent data do not establish a link between vaccination and
disease exacerbations, and there are no convincing data to support
withholding immunizations for example, for influenza or hepatitis.

Effect of Pregnancy on the Course

• MS is a disease that predominantly affects women and has a
maximum incidence during childbearing years. The influence of
pregnancy on MS has been repeatedly examined, with evidence
that relapses are reduced during pregnancy and are more frequent
than expected in the 3-month postpartum period
• There is general agreement that the overall prognosis is no
different in women who have been pregnant, compared with those
who have not.
• Studies of women with MS reveal no increase in stillbirths, ectopic
pregnancies, or spontaneous abortions.
• These data would suggest that pregnancy has no ill effect on MS
and that MS has no negative effect on the fetus or the course of
pregnancy.

PROGNOSIS
Although great individual variability exists with regard to disease
prognosis, a variety of factors have been identified as possible prognostic
indicators.
• Sex: MS appears to follow a more benign course in women than in
men.
• Age at onset: The average age at onset of MS is 29 to

74
 32 years. Onset at an early age is seemingly a favourable factor,
whereas onset at a later age carries a less favourable prognosis. As
previously stated, the pattern of disease varies in different age
groups, with the relapsing-remitting form being more common in
younger patients and the progressive form being more common in
the older age group. Data are lacking as to whether prognosis
differs as a function of age in patients with similar patterns of
disease.
• Initial disease course: The relapsing form of the disease is
associated with a better prognosis than progressive disease.
• Initial complaints: Among initial symptoms, impairment of
sensory pathways or cranial nerve dysfunction, particularly ON,
has been found in several studies to be a favourable prognostic
feature, whereas pyramidal and particularly brainstem and
cerebellar symptoms carry a poor prognosis.

DIAGNOSTIC STUDIES
Although the diagnosis of MS remains clinical, a number of
ancillary laboratory tests can aid in the diagnosis of MS.
• Neuroimaging
 Magnetic Resonance Imaging
• MRI has significantly changed the diagnostic approach to MS
and is now the modality of choice to augment clinical
information.
• MS plaques are typicallyfound in the periventricular region,
corpus callosum, centrum semiovale and, to a lesser extent,
deep white matter structures and basal ganglia.

75
• Typical MS plaques often have an ovoid appearance and
lesions arranged at right angles to the corpus callosum as if
radiating from it (Dawson’s fingers).
• The plaques appear hyperintenseon proton density and T2-
weighted studies, whereas the plaques appear (if visible at all)
hypointense on T1-weighted images.
• Such hypointense lesions on T1-weighted scans (black holes)
are associated with axonal loss in addition to demyelination and
indicate a poorer prognosis.

76
77
• Cerebrospinal Fluid Analysis
• CSF findings alone cannot make or exclude the diagnosis of MS,
but they can be useful adjuncts to clinical criteria.
• The CSF is grossly normal in MS, being clear, colorless, and under
normal pressure.
• Total leukocyte count is normal in two thirds of patients, exceeding
15 cells/mL in less than 5% of patients and only rarely exceeding
50 cells/mL (a finding that should raise suspicion of another
etiology).
• The predominant cell type is the lymphocyte, the vast majority of
which are T cells.
• CSF protein (or albumin) level is normal in the majority of patients
with MS.
•

78
• Albumin determinations are preferable because albumin is not
synthesized in the CNS; thus this gives a better indication of BBB
disruption than does total protein, some of which may be
synthesized within the CNS (i.e., immunoglobulin).
• Albumin levels are elevated in 20% to 30% of patients, although
less than 1% of
• Evoked Potentials
• EPs, the CNS electrical events generated by peripheral stimulation
of a sensory organ, are useful in detecting a CNS abnormality of
function that may be clinically inapparent.
• In the case of MS, detection of a subclinical lesion in a site remote
from the region of clinical dysfunction supports a diagnosis of
multifocal disease.
• The EPs also may help define the anatomical site of the lesion in
tracts not easily visualized by imaging (i.e., optic nerves, dorsal
columns).
• The three most frequently used EPs are somatosensory (SSEP),
visual evoked response (VER), and brainstem auditory-evoked
responses (BAER).
• Because of its higher sensitivity and its ability to provide
anatomical information, MRI has largely eliminated the utility of
EPs in the diagnosis of MS.
• SSEPs are abnormal in 65% to 80% of patients with MS, including
approximately one half of patients with MS who do not have
sensory signs or symptoms.

79

TREATMENT AND MANAGEMENT
• In prior decades, many clinicians and patients adopted a nihilistic
and pessimistic attitude about MS because effective treatment of
this often progressive disease of young adults was unavailable.
• The advent of more effective symptomatic therapy and the widely
publicized U.S. Food and Drug Administration (FDA) approval
over the past 14 years of six agents capable of modifying the
disease course have drastically changed that view.
• Many problems remain, particularly the treatment of progressive
MS, yet there are clearly reasons for hope.

Treatment of MS should be directed toward these basic goals:

• Relief or modification of symptoms
• Shortening the duration or limiting the residual effects ofan acute
relapse
• Reducing the frequency of relapses
• Preventing progression or slowing its pace
• Supporting family and patient, alleviating social and economic
effects, and advocating for the disabled or handicapped.

• Relief or Modification of Symptoms

1) Spasticity
• Spasticity slows voluntary movement, impairs balance and gait,
and may cause painful flexor or extensor spasms.
• Partial control is often possible, although recovery of motor power
is rare.
• Baclofen is a g-aminobutyric acid agonist that can effectively
relieve spasms and has modest effects in improving performance.
Daily divided doses of 20 to 120 mg and occasionally more are
80
 used. Too large a dose may produce drowsiness or hypotonicity
sufficient to aggravate weakness, especially in those individuals
who require a degree of spasticity to stand
• Tizanidine (Zanafl ex), a centrally active a2-noradrenergic agonist,
may be used alone or in combination with baclofen because the
mechanism of action is different. The medication should be
gradually increased starting with 2 mg at bedtime.
• The Dantrolene sodium (Dantrium), an agent that acts within
muscles on excitation-contraction coupling, is rarely used because
of the risk of liver damage. If used, the medication must be titrated
from 25 mg daily up to 100 mg three times a day.
• Botulinum toxin type A (Botox) also has been shown to be
effective in selective cases.
2) Fatigue
• Fatigue occurs in as many as 78% of patients and interferes with
daily activities.
• Fatigue must be separated from depression, medication side
effects, and physical exhaustion from gait alterations.
• Amantadine (Symmetrel), 100 mg twice a day, has relatively few
side effects and is well tolerated by most patients. Caution must be
taken in patients with renal insufficiency or seizure disorders.
Studies have found an efficacy rate of 40%.
• Modafinil (Provigil) is a wakefulness-promoting agent that is
chemically and pharmacologically distinct from CNS stimulants,
although the precise mechanism of action is unknown.

81
 3) Depression
• Prevalence rates for depression in patients with MS range from
14% to 57%, as compared with 1.3% to 3.7% in the general
population.
• The lifetime prevalence of depression in a group of patients with
chronic medical disorders was 12.9%.
• The nature of a chronic debilitating neurological disorder
contributes to depressive symptoms and coping problems.
• Patients taking multiple medications are prone to depression, and
the side effect profile of the interferon-beta medications includes
depression.
• Selective serotonin reuptake inhibitors are the medications of
choice for depressive symptoms in patients with MS.
• In additionto the previously mentioned fluoxetine, any of the other
medications in this class may be used.
4) Sexual Dysfunction
• Studies suggest that 45% to 74% of women with MS experience
sexual dysfunction. These symptoms have been associated with
depression, bowel dysfunction, fatigue, spasticity, and pelvic floor
weakness.
• There was no association between duration of disease, type of
disease, recent exacerbations, or disability scores.
• Erectile dysfunction in men is common, especially in patients with
spinal cord involvement. Adverse effects of medication or
psychological issues may also be associated with sexual
dysfunction.

82
 • Sildenafil (Viagra) and similar medications have supplanted older
approaches to erectile dysfunction in men, which included
intracavernous papaverine, prostaglandin E, phentolamine, vacuum
devices, and penile prostheses. Sildenafil in doses of 25 to 100 mg
1 hour before sexual intercourse is used with minimal side effects,
which include headache, flushing, dyspepsia, and musculoskeletal
pain. Reports suggest caution in patients with cardiovascular
disease.
.
5) Paroxysmal Symptoms
• Paroxysmal symptoms in MS consist of brief, almost stereotypical,
events occurring frequently and often triggered by movement or
sensory stimuli. They are likely caused by ephaptic transmission of
nerve impulses at sites of previous disease activity.
• These symptoms include, but are not limited to, trigeminal
neuralgia, pain, paresthesia, weakness, tonic seizures, dysarthria
and ataxia, pruritus, diplopia, akinesia, hemifacial spasm, and
dystonia.
• Anticonvulsants have been used in their usual or lower doses with
some benefit. Benzodiazepines also have been effective in some
patients. Baclofen, acetazolamide (Diamox), ibuprofen, and
bromocriptine have been cited as potentially beneficial with these
paroxysmal symptoms.
• Treatment of Acute Attacks
• Acute attacks are typically treated with corticosteroids.
• Indications for treatment of a relapse include functionally
disabling symptoms with objective evidence of neurological
impairment.
• Thus, mild sensory attacks are typically not treated.

83
 • treatment with short courses of intravenous methylprednisolone,
500 to 1000 mg daily for 3 to 7 days, with or without a short
prednisone taper, has commonly been used.
•
• Disease-modifying Treatments
As of April 2013, eight disease-modifying treatments have been approved
by regulatory agencies of different countries. The approved drugs are
interferon beta-1a, interferon beta-1b, glatiramer acetate,
mitoxantrone, natalizumab, fingolimod, teriflunomide and dimethyl
fumarate

• The first medication approved by the FDA for use in MS was

recombinant interferon beta-1b (Betaseron), which was shown in a
1993 double-blind, placebo-controlled trial of 372 patients to
decrease the frequency of relapses by 34% after 2 years in
relapsing-remitting patients receiving 8 mIU every other day.
• In treated patients, the MRI T2 lesion burden increased 3.6% over
5 years, compared with 30.2% in the placebo group.
• No significant change in disease progression occurred over 5 years.
Interferon beta-1b is administered subcutaneously every other day
by self-injection. Side effects include
• influenza-like symptoms, which usually diminish over weeks to
months, depression, and reactions at the injection site. Elevated
liver enzymes, leukopenia, and anemia were seen, and blood
monitoring is recommended every 3 months.
•
Avonex interferon beta-1a :Weekly intramuscular injections of 6 million U
(30 mg)
Rebif: Subcutaneous interferon beta-a 22 mg, or 44 mg of interferon beta-1a three times a
week.
glatiramer acetate (Copaxone), 20 mg SC daily

84

OTHER INFLAMMATORY DEMYELINATING DISEASES OF THE
1. Devic’s Disease (Neuromyelitis Optica)
• A combination of bilateral optic neuropathy and myelopathy
characterize this condition, which many authorities now classify as
a separate entity rather than a variant of MS.
• The myelopathy tends to be more severe than typically occurs with
MS, with less likelihood of recovery.
• The neuropathological features at autopsy are those of a much
more severe necrotic lesion of the cord rather than incomplete
demyelination.
• In some patients the optic neuropathy and the myelopathy occur at
the same time; in others one or the other component is delayed.
Recent findings of an antibody to the aquaporin-4 water channel in
a high frequency of patients with the clinical characteristics of
Devic’s disease and low frequency in typical MS, suggests that
these may be different conditions.

2. Acute and Subacute Transverse Myelitis

• Acute and subacute transverse myelitis is defined as the
development of isolated spinal cord dysfunction over hours or days
in patients in whom no evidence exists of a compressive lesion.
• In the combined experience of several series reviewing complete
transverse myelitis, 37% of patients reported a preceding febrile
illness. The initial symptoms are paresthesias, back pain, or leg
weakness; 37% of patients had the maximal deficit within 1 day,
45% in 1 to 10 days, and 18% in more than 10 days.
• Outcome was rated as good in 42%, fair in 38%, and poor in 20%.
The prognosis may be worse in the rapid-onset group of patients.
• Only approximately 7% of patients develop MS by clinical criteria.
• Whether these cases represent a homogeneous entity remains
highly questionable, particularly because the ages of reported cases
range from 4 to 83 years.
• In addition, acute transverse myelitis is known to occur on a
background of systemic vasculitis, such as that seen in SLE and
that associated with heroin abuse.
• One must distinguish complete transverse myelitis from the partial
or incomplete syndromes that more frequently predict evolution to
MS in 50% to 90% of patients. treatment with short courses of
intravenous methylprednisolone, 500 to 1000 mg daily for 3 to 7

85
 days, with or without a short prednisone taper, has commonly been
used

3. Optic Neuritis
• The clinical features of ON are described in the section on MS. In
ON associated with MS, the majority of clinical episodes are
unilateral, although VERs also may indicate involvement of the
contralateral eye.
• Simultaneous bilateral ON is rare in MS and somewhat more
frequent in Devic’s disease.
• The estimated incidence of subsequent development of MS
following an initial episode of ON varies widely among different
series (from less than 20% to more than 70%).
• The issue remains whether some cases of isolated ON do represent
formes frustes of ADEM. In this regard, cases of ON occurring
after childhood exanthemas would represent the best example of
parainfectious ON. Cases have been reported following measles,
rubella, mumps, and varicella.
• The young age of the patients further suggests that these events are
not the initial manifestations of MS. The prognosis for recovery of
vision is good in most cases, perhaps less so in postvaricella cases.
treatment with short courses of intravenous methylprednisolone,
500 to 1000 mg daily for 3 to 7 days, with or without a short
prednisone taper, has commonly been used

86
 Peripheral neuropathy (PN)

(Dr. Ibrahim Alahmar)

Peripheral neuropathy (PN) is damage or disease affecting

nerves, which may impair sensation, movement, gland or organ
function, or other aspects of health, depending on the type of nerve
affected.
• In conventional medical usage, the word neuropathy (neuro-,
"nervous system" and -pathy, "disease of") without modifier
usually means peripheral neuropathy.
• Peripheral neuropathy may affect Motor nerves (that control
muscles), sensory nerves, or autonomic nerves (that control
automatic functions such as heart rate, body temperature and
breathing).
• More than one type of nerve may be affected at the same time.
• causes :
- inherited (present from birth).
- systemic diseases (such as diabetes or leprosy)
- vitamin deficiency
- medication (e.g., chemotherapy)
- traumatic injury
- excessive alcohol consumption
- immune system disease
- Infection

Classification:
-Peripheral neuropathies may be classified according to:

87
1- The type of nerve predominantly involved (motor, sensory,
autonomic)

Neuronopathies and Neuropathies with Predominantly Motor

Manifestations
1. Multifocal motor neuropathy*
2. Guillain-Barré syndrome
3. Acute motor axonal neuropathy*
4. Porphyric neuropathy
5. Chronic infl ammatory polyradiculoneuropathy
6. Neuropathy with osteosclerotic myeloma
7. Diabetic lumbar radiculoplexopathy
8. Hereditary motor sensory neuropathies (Charcot-Marie-Tooth disease)
9. Lead intoxication
*Pure motor syndromes with normal sensory nerve action potentials

2- The number and distribution of nerves affected (mononeuropathy,

mononeuritis multiplex or polyneuropathy).

• Neuropathy affecting just one nerve is called "mononeuropathy"

• Neuropathy involving multiple nerves in roughly the same areas
on both sides of the body is called "symmetrical polyneuropathy"
or simply “polyneuropathy”
• When two or more (typically just a few, but sometimes many)
separate nerves in disparate areas of the body are affected it is
called “mononeuritis multiplex" "multifocal mononeuropathy"
or "multiple mononeuropathy.

Causes of Multiple Mononeuropathies:-
• Axonal injury
• Vasculitis (systemic, nonsystemic)
• Diabetes mellitus
• Sarcoidosis
• Hansen’s disease (leprosy)
• Human immunodeficiency virus 1 infection
• Demyelination/conduction block
• Multifocal acquired demyelinating sensory and motor neuropathy
• Multifocal motor neuropathy
• Multiple compression neuropathies (hypothyroidism, diabetes)
• Hereditary neuropathy with liability to pressure palsies

3- The underlying cause:

• Peripheral neuropathies are common neurological problems caused
by disordered function and structure of peripheral motor, sensory,
and autonomic nerves.

88
 • The causes of neuropathies are disparate and their clinical
presentations highly variable.
• The main causes of neuropathy are entrapment, diabetes, and
other systemic diseases; inherited disorders; infl amatory
demyelinating, ischemic, and paraneoplastic conditions; defi
ciency states; infections; and toxins.
• A logical systematic diagnostic approach to peripheral
neuropathies consists of a (1) careful history, (2) detailed physical
and neurological examination, and (3) electrophysiological studies,
which not only confirm the presence of a peripheral nerve disorder
but also shorten the list of diagnostic possibilities.
• The process affecting the nerves; e.g., inflammation (neuritis),
compression (compression neuropathy), chemotherapy
(chemotherapy-induced peripheral neuropathy). Where the cause is
unknown it is described as idiopathic neuropathy.

• Onset of Peripheral neuropathy may be chronic (a long-term

condition where symptoms begin subtly and progress slowly) or
acute (sudden onset, rapid progress and slow resolution). Acute
neuropathies demand urgent diagnosis.

Clinical pictures:
• Neuropathy may cause painful cramps, fasciculations (fine muscle
twitching), muscle loss, bone degeneration, and changes in the
skin, hair, and nails.
• Additionally, motor neuropathy may cause impaired balance and
coordination or, most commonly, muscle weakness; sensory
neuropathy may cause numbness to touch and vibration, reduced
position sense causing poorer coordination and balance, reduced
sensitivity to temperature change and pain, spontaneous tingling or
burning pain, or skin allodynia (severe pain from normally
nonpainful stimuli, such as light touch); and autonomic
neuropathy may produce diverse symptoms, depending on the
affected glands and organs, but common symptoms are poor
bladder control, abnormal blood pressure or heart rate, and reduced
ability to sweat normally.

Classification:

89
 1-Mononeuropathy

• Definition: is a type of neuropathy that only affects a single nerve.

• It is diagnostically useful to distinguish it from polyneuropathy
because the limitation in scope makes it more likely that the cause
is a localized trauma or infection.
• The most common cause of mononeuropathy is physical
compression of the nerve, known as compression neuropathy.
Carpal tunnel syndrome and axillary nerve palsy are examples of
this.
• The "pins-and-needles" sensation of one's "foot falling asleep"
(paresthesia) is caused by a compression mononeuropathy, which
can be resolved merely by moving around and adjusting to a more
appropriate position.
• Direct injury to a nerve, interruption of its blood supply (ischemia),
or inflammation can also cause mononeuropathy.

2-Mononeuritis multiplex

• Definition: (occasionally termed polyneuritis multiplex) is

simultaneous or sequential involvement of individual
noncontiguous nerve trunks, either partially or completely,
evolving over days to years and typically presenting with acute or
subacute loss of sensory and motor function of individual nerves.
• Clinical picture: The pattern of involvement is asymmetric;
however, as the disease progresses deficit(s) becomes more
confluent and symmetrical, making it difficult to differentiate from
polyneuropathy.
• Therefore, attention to the pattern of early symptoms is important.
• Mononeuritis multiplex may also cause pain, which is
characterized as deep, aching pain that is worse at night and
frequently in the lower back, hip, or leg.
• In people with diabetes mellitus, mononeuritis multiplex is
typically encountered as acute, unilateral, severe thigh pain
followed by anterior muscle weakness and loss of knee reflex.
• Electrodiagnostic studies will show multifocal sensory motor
axonal neuropathy.
• Causes: It is caused by, or associated with, several medical
conditions:

- diabetes mellitus

90
 - vasculitides: polyarteritis nodosa, Wegener's granulomatosis, and
Churg–Strauss syndrome

- immune-mediated diseases like rheumatoid arthritis, lupus

erythematosus (SLE)

- infections: leprosy, lyme disease, HIV

- sarcoidosis, amyloidosis

- cryoglobulinemia

- chemical agents, including trichloroethylene and dapsone

- rarely, the sting of certain jellyfish, such as the sea nettle

3-Polyneuropathy

• Definition: is a pattern of nerve damage which is quite different

from mononeuropathy, often more serious and affecting more
areas of the body.
• The term "peripheral neuropathy" is sometimes used loosely to
refer to polyneuropathy.
• In cases of polyneuropathy, many nerve cells in various parts of
the body are affected, without regard to the nerve through which
they pass; not all nerve cells are affected in any particular case.
•
• In distal axonopathy, one common pattern is that the cell bodies
of neurons remain intact, but the axons are affected in
proportion to their length.
• Diabetic neuropathy is the most common cause of this pattern.
• In demyelinating polyneuropathies, the myelin sheath around
axons is damaged, which affects the ability of the axons to
conduct electrical impulses.
• The third and least common pattern affects the cell bodies of
neurones directly.
• This usually picks out either the motor neurones (known as
motor neurone disease) or the sensory neurones (known as
sensory neuronopathy or dorsal root ganglionopathy).
• The effect of this is to cause symptoms in more than one part of
the body, often on left and right sides symmetrically.
• As for any neuropathy, the chief symptoms include weakness or
clumsiness of movement (motor); unusual or unpleasant

91
 sensations such as tingling or burning; reduction in the ability to
feel texture, temperature, etc.; and impaired balance when
standing or walking (sensory).
• In many polyneuropathies, these symptoms occur first and most
severely in the feet.
• Autonomic symptoms may also occur, such as dizziness on
standing up, erectile dysfunction, and difficulty controlling
urination.
• Polyneuropathies are usually caused by processes that affect the
body as a whole.
• Diabetes and impaired glucose tolerance are the most common
causes.
• Other causes relate to the particular type of polyneuropathy, and
there are many different causes of each type, including
inflammatory diseases such as lyme disease, vitamin
deficiencies, blood disorders, and toxins (including alcohol and
certain prescribed drugs).
• Most types of polyneuropathy progress fairly slowly, over
months or years, but rapidly progressive polyneuropathy also
occurs.
• It is important to recognize that glucose levels in the blood can
spike to nerve-damaging levels after eating even though fasting
blood sugar levels and average blood glucose levels can still
remain below normal levels (currently typically considered
below 100 mg/dL for fasting blood plasma and 6.0% for
HGBA1c, the test commonly used to measure average blood
glucose levels over an extended period).
• Studies have shown that many of the cases of peripheral small
fiber neuropathy with typical symptoms of tingling, pain, and
loss of sensation in the feet and hands are due to glucose
intolerance before a diagnosis of diabetes or pre-diabetes. Such
damage is often reversible, particularly in the early stages, with
diet, exercise, and weight loss.
• The treatment of polyneuropathies is aimed firstly at
eliminating or controlling the cause, secondly at maintaining
muscle strength and physical function, and thirdly at controlling
symptoms such as neuropathic pain.

Autonomic neuropathy

• Autonomic neuropathy is a form of polyneuropathy which affects

the non-voluntary, non-sensory nervous system (i.e., the autonomic

92
 nervous system), affecting mostly the internal organs such as the
bladder muscles, the cardiovascular system, the digestive tract, and
the genital organs.
• These nerves are not under a person's conscious control and
function automatically.
• Autonomic nerve fibers form large collections in the thorax,
abdomen, and pelvis outside the spinal cord. However, they have
connections with the spinal cord and ultimately the brain.
• Most commonly autonomic neuropathy is seen in persons with
long-standing diabetes mellitus type 1 and 2.
• In most but not all cases, autonomic neuropathy occurs alongside
other forms of neuropathy, such as sensory neuropathy.

Neuropathies with Autonomic Nervous System Involvement

ACUTE
• Acute panautonomic neuropathy (idiopathic, paraneoplastic)
• Guillain-Barré syndrome
• Porphyria
• Toxic: vincristine
CHRONIC
• Diabetes mellitus
• Amyloid neuropathy (familial and primary)
• Paraneoplastic sensory neuropathy (malignant infl amatory sensory polyganglionopathy)
• Human immunodeficiency virus-related autonomic neuropathy
• Hereditary sensory and autonomic neuropathy

• Autonomic neuropathy is one cause of malfunction of the

autonomic nervous system but not the only one; some conditions
affecting the brain or spinal cord can also cause autonomic
dysfunction, such as multiple system atrophy, and therefore cause
similar symptoms to autonomic neuropathy.

The signs and symptoms of autonomic neuropathy include the following:

• Urinary bladder conditions: bladder incontinence or urine retention

• Gastrointestinal tract: dysphagia, abdominal pain, nausea, vomiting,
malabsorption, fecal incontinence, gastroparesis, diarrhoea,
constipation
• Cardiovascular system: disturbances of heart rate (tachycardia,
bradycardia), orthostatic hypotension, inadequate increase of heart
rate on exertion
• Respiratory system: impairments in the signals associated with
regulation of breathing and gas exchange (central sleep apnea,
hypopnea, bradypnea).[6]
• Other areas: hypoglycemia unawareness, genital impotence, sweat
disturbances

93
Charcot-Marie-Tooth Disease (Hereditary Motor and Sensory
Neuropathy)

• Charcot and Marie in Paris, and Tooth in London first described

the syndrome of peroneal muscular atrophy, or CMT disease, in the
second half of the nineteenth century.
• CMT disease is the most common inherited neuropathy, with an
estimated prevalence of 1 in 2500 in the United States.
• Clinical studies combined with electrophysiological and sural
nerve biopsy investigations of a large number of families with
peroneal muscular atrophy has allowed a separation into two main
groups
o The Demyelinating Form Or CMT1, (formerly hereditary motor
and sensory neuropathy [HMSN] type I) in which there is
marked reduction in motor NCVs and nerve biopsy findings
of demyelination and onion bulb formation; and
o The Axonal Form Of CMT Disease Or CMT2 (formerly
HMSNtype II), in which motor NCVs are normal or near
normal and nerve biopsy reveals axonal loss without
demyelination.
• The peroneal muscular atrophy phenotype without sensory
involvement on either clinical or electrophysiological examination
has been classified as hereditary distal spinal muscular atrophy.
• A more severe form of demyelinating neuropathy with onset
occurring in early childhood is referred to as Dejerine-Sottas
disease.
• Both CMT1 and CMT2 display autosomal dominant inheritance.
• A minority of cases occur sporadically or in siblings only and have
therefore been attributed to autosomal recessive inheritance or to
de novo gene mutations. Because a great variability in clinical
expression exists among affected kin
• In the dominant disorders, a recessive inheritance can only be
accepted if the clinical and electrophysiological examinations of
both parents have proved to be normal; even when the cause is non
parental most of these patients phenotypically resemble CMT1. For
any of these groups, an ever-increasing number of genetic subtypes
have been described.

• Charcot-Marie-Tooth Disease 1
• In CMT1, symptoms often begin during the first or second decade
of life. Slowly progressive weakness, muscular wasting, and

94
 sensory impairment predominantly involving the distal legs
characterize it.
• Foot deformities and difficulties in running or walking resulting
from symmetrical weakness and wasting in the intrinsic foot,
peroneal, and anterior tibial muscles are often present. In two thirds
of the patients the upper limbs are involved later in life.
• Inspection reveals pes cavus and hammer toes in nearly three
quarters of adult patients; mild kyphosis in approximately a tenth;
and palpably enlarged, hypertrophic peripheral nerves in a quarter.
• The foot deformities occur because of long-term muscular
weakness and imbalance between the intrinsic extensor and long
extensor muscles of the feet and toes (a similar process causes
clawing of the fingers in more advanced cases).
• Absent ankle reflexes are universal and frequently associated with
absent or reduced knee and upper limb reflexes.
• Some degree of distal sensory impairment (diminished vibration
sense and light touch in the feet and hands) is usually discovered
by examination, but rarely gives rise to symptoms.
• Occasionally, patients have an essential or postural upper limb
tremor. Such cases have been referred to as Roussy-Lévy
syndrome, but current evidence suggests that this is not a separate
clinical or genetic entity. Motor nerve conduction studies show
uniform slowing by more than 25% of the lower limits of normal in
all nerves.
• Motor conduction of upper limb nerves proves more useful than
studies of lower extremity nerves because distal denervation in the
feet is often severe and virtually complete.
• A conduction velocity below 38 m per second in the forearm
segment of the median nerve is proposed as a cut off value to
distinguish between CMT disease types 1 and 2.
• Although this cut off is useful, it can be misleading if applied too
rigidly. Sensory conductions are similarly abnormal.
•
•
• SNAPs are usually absent with surface recordings.
• Routine hematological and biochemical studies are normal. CSF is
also normal, which helps differentiate the condition from chronic
inflammatory demyelinating poly neuropathy, in which the CSF
protein is usually elevated.
• Sural nerve biopsy typically shows the changes of a hypertrophic
neuropathy characterized by onion bulb formation, increased
frequency of fibers with demyelinated and remyelinated segments,

95
 an increase in endoneurial area, and loss of large myelinated fibers
.
• Gene mutations, predominantly affecting genes for myelin and
Schwann cell proteins, have been recognized that account for about
three quarters of families with CMT1

Leg atrophy, pes cavus, and enlarged great auricular nerve (arrow) areevident in a patient with
Charcot-Marie-Tooth type 1 disease
.

Treatment and Management

• The rates of progression of CMT1 and CMT2 are slow, disability
occurs relatively late, and life span may be normal.
• Management is mainly symptomatic.
• Patients should be instructed in proper foot care and advised to
wear broad, well-fitting shoes.
• Insoles may be used to distribute body weight more evenly in
patients with a foot deformity.
• Ankle-foot braces or orthopaedic procedures are indicated to
correct for severe foot drop.

96
• Patients should be warned to avoid neurotoxic drugs because of
greater susceptibility to agents such as vincristine.
• Issues like genetic counselling, family planning, prenatal diagnosis,
and psychological concerns must be carefully approached,
preferably by a multidisciplinary team, including a genetic
counsellor.

Phytanic Acid Storage Disease (Refsum’s Disease)

• Refsum’s disease, heredopathia atactica polyneuritiformis, is a rare
autosomal recessive disorder of phytanic acid metabolism.
• The gene defect has been localized to chromosome 10 and encodes
the peroxisomal enzyme phytanoyl-CoA-hydroxylase.
• The defect in the enzyme that initiates the alpha-oxidation
pathway of b-methyl substituted fatty acids leads to phytanic acid
accumulation in serum and tissues.
• Phytanic acid is derived exclusively from dietary sources, mainly
chlorophyll, dairy products, meats, and fish oils. Clinical onset
spans from childhood to the third decade of life.
• The cardinal manifestations include pigmentary retinal
degeneration, with night blindness or visual field constriction,
chronic hypertrophic neuropathy, ataxia, and other cerebellar signs
such as nystagmus and intention tremor.
• Initially, the neuropathy affects the lower limbs with distal leg
atrophy, weakness, areflexia, large-fiber sensory impairment, and
sometimes palpably enlarged nerves.
• Weakness becomes generalized later in the illness. In addition to
pes cavus, overriding toes caused by symmetrically short fourth
metatarsals are a helpful sign for Refsum’s disease.
• Progressive sensorineural hearing loss, anosmia, cardiomyopathy,
and ichthyosis are common.
• The course may be either progressive or fluctuating with
exacerbations and remissions. Exacerbations are often precipitated
by fasting, which mobilizes phytanic acid from endogenous fat
stores.
• Motor conduction velocities are markedly slowed, and SNAPs are
reduced or absent.
• CSF protein is increased in the range of 100 to 700 mg/dL. Sural
nerve biopsy reveals a hypertrophic neuropathy with prominent
onion bulb formation.
• The diagnosis is confirmed by elevated serum levels of phytanic
acid.

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 • Chronic dietary treatment, by restricting the exogenous sources of
phytanic acid (<10 mg/day) and its precursor phytol, results in
reduction of serum phytanic acid levels and clinical improvement.
• The diet should provide sufficient calories to avoid weight loss.
• Plasma exchange has been used to lower toxic serum phytanic acid
levels more rapidly in critically ill patients.

Acute Infl ammatory Demyelinating Polyradiculoneuropathy

(Guillain-Barré Syndrome)
• In 1916, Guillain, Barré, and Strohl emphasized the main clinical
features of GBS: motor weakness, areflexia, paresthesias with
minor sensory loss, and increased protein in CSF without
pleocytosis (albuminocytological dissociation).
• The frequent finding of motor conduction block and reduced NCVs
provided further electrophysiological confirmation of the
widespread demyelination.

• Diagnostic Criteria for Guillain-Barré Syndrome

• Features required for diagnosis
1. Progressive ascending proximal weakness of both legs and arms
2. A reflexia
• Clinical features supportive of diagnosis
1. Progression over days to 4 wk
2. Relative symmetry of signs
3. Mild sensory symptoms or signs
4. Cranial nerve involvement (bifacial palsies)
5. Recovery beginning 2-4 wk after progression ceases
6. Autonomic dysfunction
7. Absence of fever at onset
• Laboratory features supportive of diagnosis
1. Elevated cerebrospinal fl uid protein with < 10 cells/mL
2. Electrodiagnostic features of nerve conduction slowing or block

• Classification of Guillain-Barré Syndrome (GBS) Subtypes

1. Acute inflammatory demyelinating polyradiculoneuropathy
2. Acute motor axonal neuropathy
3. Acute motor sensory axonal neuropathy
4. Miller-Fisher syndrome
5. Acute pandysautonomia
6. Sensory GBS

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Clinical Features
• The classical form of GBS is a non-seasonal illness that affects
persons of all ages, but males are more often affected than females
(1.5:1).
• With the virtual eradication of acute poliomyelitis, GBS has
become the leading cause of acute paralytic disease in Western
countries.
• The mean annual incidence is 1.8 per 100,000 population and has
remained stable over the past three decades.
• Incidence rates increase with age from 0.8 in those younger than 18
years to 3.2 for those 60 years and older.
• Approximately two thirds of patients report a preceding event,
most frequently an upper respiratory or gastrointestinal infection,
surgery, or immunization 1 to 4 weeks before the onset of
neurological symptoms. The agent responsible for the prodromal
illness often
Antecedent Events of Guillain-Barré Syndrome*

ANTECEDENT EVENT PERCENTAG

Respiratory illness 58
Gastrointestinal illness 22
Respiratory and gastrointestinal illness 10
Surgery 5
Vaccination 3
Other 2

SEROLOGICAL EVIDENCE OF SPECIFIC INFECTIOUS

AGENTS

Campylobacter jejuni 26
Cytomegalovirus 15
Epstein-Barr virus 8
Mycoplasma pneumoniae 10

• Patients with classic GBS may initially present with weakness,

with or without paresthetic sensory symptoms
• .The fairly symmetrical weakness of the lower limbs ascends
proximally over hours to several days and may subsequently
involve arm, facial, and oropharyngeal muscles, and, in severe
cases, respiratory muscles.
• Its severity varies from mild, in which patients are still capable of
walking unassisted, to a nearly total quadriplegia.
• Hyporeflexia or areflexia are the invariable features of GBS but
may be absent early in the course of the disease.

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• By definition, progression of the clinical process ends by 1 to 4
weeks into the illness.
• Cranial nerve involvement has occurred in 45% to 75% of cases in
different series.
• Facial paresis, usually bilateral, is found in at least in one half of
patients. The proportion of patients developing respiratory failure
and requiring assisted ventilation seems to increase with age and
ranges from 12% in epidemiological series to 30% in hospital-
based series.
• Sensory loss is not a prominent feature and is frequently limited to
the distal impairment of vibration sense.
• Moderate to severe pain occurs in 85% of patients on admission to
the hospital.
• Interscapular or low back pain with radiation into the legs is most
common, sometimes raising concern about the possibility of an
epidural hematoma or abscess.
• Dysesthetic pain described as burning or tingling of the limbs is
present in approximately one half of patients.
• Unusual clinical variants with restricted patterns of weakness may
cause diagnostic difficulty. Isolated weakness of the face,
oropharynx, neck, and arms without involving the legs is a
distinctive feature of the pharyngeal-cervical-brachial variant.
• Most of the clinically significant autonomic dysfunction occurs
within the first 2 to 4 weeks of the illness, the peak period of
paralysis. Its varied and complex manifestations may be related to
either increased or decreased sympathetic parasympathetic activity,
resulting in orthostatic hypotension, urinary retention,
gastrointestinal atony, iridoplegia, episodic or sustained
hypertension, sinus tachycardia, tachyarrhythmias, anhidrosis or
episodic diaphoresis, and acral vasoconstriction.
• Excessive vagal activity accounts for sudden episodes of
bradycardia, heart block, and asystole.
• These “vagal spells” may occur spontaneously or may be triggered
by tracheal suctioning or similar stimuli.
• Serious cardiac arrhythmias with hemodynamic instability tend to
be more frequent in patients with severe quadriparesis and
respiratory failure. Autonomic dysfunction can result in
electrocardiographical changes including T-wave abnormalities,
ST-segment depression, QRS widening, QT prolongation, and
various forms of heart block.

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Treatment
• Patients with rapidly worsening acute GBS should be observed in
the hospital until the maximum extent of progression has been
established.
• The reduction in mortality to less than 5% reflects improvements in
modern critical care.
• Supportive care in intensive care units and the prevention of
complications, of which respiratory failure and autonomic
dysfunction are the most important, provide the best chance for a
favorable outcome.
• Respiratory and bulbar function, the ability to handle secretions,
heart rate, and blood pressure, should be closely monitored during
the progressive phase. Respiratory failure requiring mechanical
ventilation develops in up to 30%of patients with GBS.
• Subcutaneous heparin or low-molecular-weight heparin together
with calf compression devices should be ordered routinely in
immobilized patients to lower the risks of venous thrombosis and
pulmonary embolism.
• Infections of the lung and urinary tract develop in almost half of
patients with GBS in the intensive care unit.
• Prevention and prompt treatment of nosocomial infections are
important aspects of care.
• Chest physical therapy and frequent oral suctioning aid in
preventing atelectasis in patients with impaired cough and sigh.
Skilled nursing care with regular turning and attention to skin,
eyes, mouth, bowel, and bladder are essential. Exposure keratitis is
avoided

• Among specific therapeutic interventions aimed at mitigating the

harmful effects of autoantibodies, plasma exchange and high-dose
intravenous immune globulin (IVIG) infusions five daily infusions
of immunoglobulin (0.4 g/kg/day) given in the first 2 weeks of the
disease have been shown to be equally effective.
• Benefits are clearest when plasma exchange is begun within 2
weeks of onset. The recommended plasmapheresis schedule entails
a series of five exchanges (40 to 50 mL/kg) with a continuous flow
machine on alternate days using saline and albumin as replacement
fluid.

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Diabetic Neuropathies
• The complications specific to diabetes include retinopathy,
nephropathy, and neuropathy. Patients with all forms of diabetes of
sufficient duration, whether insulin-dependent (IDDM) or non-
insulin–dependent diabetes (NIDDM), are vulnerable to these
complications.
• Diabetic neuropathy is defined as the presence of symptoms and
signs of peripheral nerve dysfunction in individuals with diabetes
after the exclusion of other causes. In addition, diabetic
neuropathies, being common disorders, may coincide with other
conditions that cause similar manifestations including CIDP,
vitamin B12 deficiency, alcoholic neuropathy, and endocrine
neuropathies.

Classification of Diabetic Neuropathies

• SYMMETRICAL POLYNEUROPATHIES
1. Distal sensory or sensorimotor polyneuropathy
2. Small-fiber neuropathy
3. Autonomic neuropathy
4. Large-fiber neuropathy
• ASYMMETRICAL NEUROPATHIES
1. Cranial neuropathy (single or multiple)
2. Truncal neuropathy (thoracic radiculopathy)
3. Limb mononeuropathy (single or multiple)
4. Lumbosacral radiculoplexopathy (asymmetrical proximal motor neuropathy)
5. Entrapment neuropathy
• COMBINATIONS
1. Polyradiculoneuropathy
2. Diabetic neuropathic cachexia
3. Symmetrical polyneuropathies

Pathogenesis of Diabetic Neuropathy

• Although the causes of diabetic neuropathies remain unknown,
currently accepted hypotheses focus on the possibilities of
metabolic and ischemic factors and their interactions in causing
nerve injury.
• Hyperglycemia has been implicated in many different pathogenic
mechanisms in diabetic neuropathy, but there is also a role for
insulin defciency and its effect on neurotrophic factors in the
pathogenesis of neuropathy.
• Hyperglycemia generates rheological changes that increase
endoneurial vascular resistance and reduce nerve blood flow.
Hyperglycemia also causes depletion of nerve myoinositol through

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 a competitive uptake mechanism and activates protein kinase C.
reductase, which leads to the accumulation of sorbitol and fructose
in nerve and enhancement of non enzymatic glycosylation of
structural nerve proteins. Another adverse effect of hyperglycemia
is autooxidation of glucose, which results in the generation of toxic
reactive oxygen intermediates.

Clinical Feature

1. Distal Symmetrical Polyneuropathy

• Distal symmetrical polyneuropathy is the most common form of
diabetic neuropathies. Many physicians incorrectly assume that the
term diabetic neuropathy is synonymous with distal symmetrical
polyneuropathy, because the latter constitutes perhaps three fourths
of all diabetic neuropathies. In distal symmetric polyneuropathy
sensory deficits predominate, and autonomic symptoms usually
correlate with the severity of the neuropathy.
• Most patients will develop only a minor motor involvement
affecting the distal muscles of the lower extremities.
• Sensory disturbances have a stocking-glove distribution followinga
length- dependant pattern. Early sensory manifestations begin in
the toes, gradually spreading proximally; when these reach above
knee level, the fi ngers and hands become affected.
• The distal symmetrical polyneuropathy may be subclassified
further into two major subgroups, depending on the nerve fiber
type most involved: large-fiber and small-fiber variants.
• The large-fiber variant presents with painless paresthesias
beginning at the toes and feet, impairment of vibration and joint
position sense, and diminished muscle stretch refl exes. In
advanced cases, significant ataxia may develop due to sensory
deafferentation.

• In contrast to the large-fiber neuropathy, the small-fiber variant

frequently presents with pain of a deep, burning, stinging, aching
character, often associated with spontaneous shooting pains and
allodynia to light touch. Pain and temperature modalities are
impaired with relative preservation of vibration and joint position
sensation and muscle stretch reflexes. The small fiber variant is
often accompanied by autonomic neuropathy
• At times, a painful small-fiber neuropathy develops soon after the
onset of IDDM.

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 • It is now clear that peripheral neuropathy can occur before the
onset of clinically diagnosable diabetes mellitus, so-called
impaired glucose tolerance neuropathy. Individuals with impaired
glucose tolerance, as determined by oral glucose tolerance testing
(OGTT), have been demonstrated to have symptoms,
electrophysiological abnormalities, and intraepidermal nerve fiber
density reduction consistent with a predominantly small-fiber
neuropathy, although with changes less pronounced than in their
diabetic counterparts
• The implication for clinical practice is that patients with
undiagnosed painful peripheral neuropathy should undergo OGTT
and that early diagnosis followed by improved life-style may result
in reversal of impaired glucose tolerance and, intuitively, of
neuropathy.
• An acute painful neuropathy may be precipitated following the
initiation of treatment of a diabetic patient with insulin(treatment-
induced neuropathy). Burning pain and paresthesias develop in the
distal lower extremities shortly after the establishment of glucose
control. Pain persists for weeks or up to several months with
spontaneous resolution to follow.
2. Diabetic Autonomic Neuropathy
• Autonomic neuropathy usually correlates with the severity of
somatic neuropathy. The spectrum of autonomic involvement
ranges from subclinical functional impairment of cardiovascular
reflexes and sudomotor function to severe
cardiovascular,gastrointestinal, or genitourinary autonomic
dysfunction.

• Orthostatic hypotension (rarely symptomatic), resting tachycardia,

or diminished heart rate response to respiration are the hallmarks of
diabetic cardiac autonomic neuropathy. Orthostatic hypotension
occurs mainly because of failure of the sympathetic nervous system
to increase systemic vascular resistance in the erect posture and
impairment of compensatory cardiac acceleration.
• Vagal denervation of the heart results in a high resting pulse rate
and loss of sinus arrhythmia.
• An increased incidence of painless or silent myocardial infarction
is reported in diabetic patients with autonomic neuropathy.
• Gastrointestinal motility abnormalities involving esophagus,
stomach, gallbladder, and bowels and fecal incontinence may
occur.

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 • Delayed gastric emptying, usually of solids, leads to nausea, early
satiety, and postprandial bloating.
• Diabetic diarrhea, due to small intestinal involvement, typically
occurs at night, and is explosive and paroxysmal. However,
constipation due to colonic hypomotility is more common than
diarrhea.. Bacterial overgrowth may occur and can often be
successfully treated with small doses of tetracycline (250 to 500
mg/day in a single dose given at the onset of a diarrheal attack) in
adult patients.
• Bladder atony leads to prolonged intervals between voiding,
gradually increasing urinary retention, and finally overflow
incontinence. The symptoms of urinary autonomic dysfunction
develop insidiously and progress slowly.
• Autonomic dysfunction involves both erectile failure and
retrograde ejaculation.
3. Asymmetrical Proximal Diabetic Neuropathy or Lumbosacral
Radiculoplexopathy
• Diabetic amyotrophy, thoracic radiculopathy, and proximal or
diffuse lower extremity weakness should probably be grouped
under the single term diabetic polyradiculopathy, since these
disorders seem to be different presentations of the same basic
involvement of multiple nerve roots or proximal nerve segments.
• Clinically, asymmetrical weakness and wasting of pelvifemoral
muscles may occur either abruptly or in a stepwise progression in
individuals with diabetes who are older than 50 years. Most
patients have NIDDM, but the onset is unrelated to the duration of
diabetes.
• Typically, unilateral severe pain in the lower back, hip, and
anterior thigh heralds the onset of neuropathy. Within days to
weeks weakness ensues, affecting proximal and, to a lesser extent,
distal, lower extremity muscles (iliopsoas, gluteus, thigh adductor,
quadriceps, hamstring, and anterior tibialis). In some cases, the
opposite leg becomes affected after a latency of days to months.
Reduction or absence of knee and ankle jerks is the rule. Numbness
or paresthesias are minor
4. Truncal Neuropathy
• Diabetic truncal neuropathy or thoracic radiculopathy involving the
T4 through T12 spinal nerve roots causes pain or dysesthesias in
areas of the chest or abdomen, thereby producing diagnostic
confusion. Bulging of the abdominal wall as a result of weakness
of abdominal muscles may also occur .This unique truncal pain is
seen in older patients with NIDDM and may occur either in

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 isolation or together with the typical lumbosacral
radiculoplexopathy.
• Patients describe burning, stabbing, boring, beltlike pain. Contact
with clothing can be very unpleasant. The onset may be either
abrupt or gradual and in some patients preceded or accompanied by
a profound weight loss.

5. Cranial Mononeuropathies

• A third-nerve palsy is the most commonly encountered diabetic

cranial mononeuropathy. Pupillary sparing, the hallmark of
diabetic third-nerve palsy, results from ischemic infarction of the
centrifascicular oculomotor axons due to diabetic vasculopathy of
the vasa nervorum. The peripherally located pupillary motor fibers
are spared as a result of collateral circulation from the
circumferential arteries.
• With decreasing frequency, the fourth, sixth, and seventh nerves
are also affected. Patients with Bell’s palsy have a significantly
higher frequency of diabetes than an age-matched population. Most
make a full recovery in 3 to 5 months.
• Two serious infectious syndromes occur occasionally in patients
with diabetes mellitus, which characteristically affect one or more
cranial nerves by local inflammation. Rhinocerebral mucormycosis
and “malignant” external otitis were often fatal before the advent
of early diagnosis and effective treatment.

Treatment
• The cornerstone in the treatment of diabetes and its complications
remains optimal glucose control. Considerable evidence supports
the idea that good diabetic control is associated with less frequent
and less severe peripheral nerve complications.
• Successful pancreatic transplantation is beneficial in preventing the
progression of diabetic neuropathy, and the effect may be sustained
in long-term follow-up
• Clinical trials of myoinositol supplementation have shown confl
icting results, and those of aldose reductase inhibitors have so far
failed to produce convincing clinical improvement or proved toxic,
though there were modest changes in nerve conduction and nerve
pathology.
• Based on experimenttal data suggesting that oxidative stress
mediated by free radical species may be involved in diabetic

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 neuropathy, two large multicenter, randomized, controlled clinical
trials of a-lipoic acid, either oral or intravenous, showed benefit in
reducing neuropathic symptoms and deficits.
• Symptomatic treatment for pain, autonomic manifestations, and the
complications of sensory loss can be offered to mitigate the impact
of neuropathic symptoms. It should be remembered that about 20%
of patients with chronic painful diabetic neuropathy of over 6
months’ duration demonstrate a complete remission of symptoms
over time.
• Patients with symptomatic orthostatic hypotension are advised to
sleep with the head of the bed elevated 6 to 10 inches. The head-up
tilt prevents salt and water losses during the night, and will combat
supine hypertension.
• Practical suggestions include drinking two cups of strong coffee or
tea with meals, eating more frequent small meals rather than a few
large ones, and increasing the daily fluid intake (>20 oz/day) and
salt ingestion (10 to 20 g/day). Elastic body stockings may be
benefi cial by reducing the venous capacitance in bed but are
poorly tolerated by many patients. Plasma volume expansion can
be achieved by fludrocortisone (0.1 to 0.6 mg/day).

Niacin Deficiency (Pellagra Neuropathy)

• Niacin (nicotinic acid, vitamin B3), an end-product of tryptophan

metabolism, is incorporated into the coenzymes nicotinamide
adenine dinucleotide (NAD) and NADPH and their reduced forms.
These coenzymes play important roles in carbohydratemetabolism.
• Dietary defi ciency of niacin is rare in developed countries, but is
seen in populations dependent on corn (maize) as the main source
of carbohydrate because corn contains little niacin or tryptophan.
Defi ciency of niacin leads to pellagra, which affects the
gastrointestinal tract, skin, and nervous system, resulting in the
triad of dermatitis, diarrhea, and dementia (3Ds).
• A distal sensorimotor polyneuropathy develops in 40% to 56% of
patients with pellagra, and, if diarrhea and skin changes are absent,
is clinically indistinguishable from thiamine-defi ciency
neuropathy.
• Nonendemic pellagra rarely occurs in patients with alcoholism or
malabsorption. Excessive conversion of tryptophan to serotonin in
carcinoid syndrome also results in niacin deficiency and pellagra.

107
• Deficiency of vitamin B6 and diets rich in neutral amino acids that
interfere with tryptophan metabolism may also cause niacin
deficiency.
• Oral nicotinic acid (50 to 250 mg/day) is sufficient to treat most
symptomatic patients. However, the response to treatment may be
incomplete.

Vitamin B12 Deficiency Polyneuropathy: Subacute Combined

Degeneration

• Cobalamin (vitamin B12) and folate are essential vitamins

necessary for effective DNA synthesis. Impaired DNA synthesis
could interfere with oligodendrocyte growth and myelin formation.
• Animal products (meat, poultry, fish, and dairy products) are the
primary dietary source of cobalamin. The average Western diet
provides an excess of the vitamin (daily requirement, 3 to 9 mg),
which is stored in the liver. Excessive intake of vitamin B12 has
not been associated with any adverse effect.
• Within the acid environment of the stomach cobalamin is released
from dietary proteins. Free cobalamin initially binds to
glycoproteins known as R-binders, which are secreted by salivary
glands and gastric mucosa. In the duodenum the cobalamin- R-
binder complex is degraded by pancreatic enzymes, and the
released cobalamin then binds avidly to intrinsic factor, a 60-kD
glycoprotein produced by gastric parietal cells. The vitamin B12-
intrinsic factor complex is absorbed by means of binding to
intrinsic factor receptors in the terminal ileum. A small portion of
ingested cobalamin is also absorbed by passive diffusion.

• Cobalamin deficiency is common in the elderly and mainly

produces pernicious anemia. This results from lack of intrinsic
factor caused by progressive autoimmune destruction of parietal
cells in the gastric mucosa. Acquired malabsorption of vitamin B12
may occur also following gastric and terminal ileal resection and
in the setting of a wide range of gastrointestinal disorders.
However, due to the large stores of cobalamin in the body it may
take several years before the symptoms of deficiency develop after
these surgeries. Unusual causes include dietary insufficiency in
strict vegetarians (vegans) and intestinal infection with fish
tapeworms.. A low level of cobalamin may be seen in pregnancy,
oral contraceptive and anticonvulsants use, and in multiple

108
 myeloma. Intraoperative use or recreational abuse of nitrous
oxide, which inactivates cobalamin-dependent enzymes, may cause
acute or subacute vitamin B12-dependent neurological disease,
particularly in patients with marginal cobalamin stores.
Prophylactic B12 injections given weeks before anesthesia will
prevent the neurological deterioration.
• The full-blown clinical picture of vitamin B12 defi ciency consists
of macrocytic anemia, atrophic glossitis, and peripheral and central
neurological complications. These last conditions include
peripheral neuropathy and optic atrophy, as well as lesions in
the posterior and lateral columns of the spinal cord (subacute
combined degeneration of the spinal cord) and in the brain.
• The neurological dysfunction may be the earliest and often the only
manifestation of vitamin B12 defi ciency. The peripheral
neuropathy results in paresthesias and large-fiber modality sensory
loss (vibration and proprioception), which may begin or be
prominent in the hands. The spinal cord manifestations consist of
posterior column damage particularly of thoracic and cervical cord,
which may include a truncal sensory level, and upper motor neuron
signs of limb weakness, spasticity, and extensor plantar responses.
The dorsal columns of the spinal cord may show a decreased signal
on T1- and increased signal on T2-weighted MRI images and
temporary contrast enhancement involving the dorsal and lateral
column may be present.

• Cerebral involvement ranges from subtle behavioral changes and

forgetfulness to dementia or stupor.
• An unsteady gait, positive Romberg’s sign reflecting a sensory
ataxia, diffuse hyperreflexia, and absent ankle jerks should raise
the suspicion of cobalamin deficiency.
• The diagnosis is confirmed by low serum vitamin B12 levels (<170
pg/mL) and normal serum folate concentration.

• Initial treatment consists of daily intramuscular injections of 1 mg

of cyanocobalamin or hydroxycobalamin for the first week,
followed by weekly injections of 1 mg, until 12 doses have
Maintenance schedules of monthly injections of 100 mg or 1 mg
every 3 months have been found satisfactory in preventing
relapses.
• This treatment corrects the anemia and may reverse the
neurological complications completely if given soon after their

109
 onset. Major neurological improvement can be expected to occur
during the first 3 to 6 months of therapy.

Neuropathy Associated with Mycobacterium leprae

• Hansen’s disease (leprosy) is a major cause of neuropathy
worldwide, especially in tropical and subtropical regions. As
improvements in public health and use of multidrug therapy have
advanced, the prevalence of Hansen’s disease in the world, as
estimated by the World Health Organization (WHO), has dropped
from 5.1 million in 1987 to less than 500,000 atthe beginning of
the year 2004.
• Leprosy remains a major challenge in the field of microbiology,
pathology, immunology and genetics, as Mycobacterium leprae
cannot be cultivated in the lab, generates an extraordinary range of
cellular immune responses, and only a small portion of any given
population is susceptible to its infection.
• M. leprae is thought to be transmitted through the upper respiratory
tract. The nasal secretions of those with lepromatous leprosy may
contain up to 2 µ 108 M. leprae in a single nose blow. Particularly
vulnerable tissue are those with mean daily temperatures in the 27°
to 30°C range, as this promotes more rapid bacterial growth.
• The skin and superficial nerve trunks of patients with leprosy are
particularly vulnerable, leading to cutaneous lesions, anesthesia,
and paralysis of face and limb muscles. The disease is classifi ed
by host reaction to infection into two polar forms, tuberculoid and
lepromatous, with three intermediate forms termed borderline
tuberculoid, intermediate borderline, and borderline lepromatous.
The Hansen bacillus has a proclivity for Schwann cells, which may
serve as a sequestered reservoir of infection with relative protection
from host defenses. The neuropathy arises not only from the
infection of peripheral nerves but also from the inflammatory and
immunological responses to this mycobacterium.
Clinical Features
• The unique propensity of M. leprae to invade cutaneous nerves and
nerve trunks causes the cardinal symptom of sensory loss.
• In tuberculoid Hansen’s disease sensory loss, initially affecting
pinprick and temperature, is detected within sharply demarcated
hypopigmented skin lesions. Adjacent cutaneous nerves or mixed
nerve trunks are apt to become involved. The body folds, being
warmer than exposed areas, are not affected. Proprioception and
motor function are largely unaffected in the early stages, so

110
 patients can still use their anesthetic limbs, which leads to painless
trauma, ulcerations, and trophic changes. Attention should be paid
to the palpation of peripheral nerves that course close to the skin
surface, including the great auricular, ulnar, radial, common fi
bular, and sural nerves, in order to detect nerve enlargement.
• Lepromatous Hansen’s disease is characterized by symmetrical
bacillary infiltration of the skin with a predilection for cooler areas
of the body, avoiding the scalp, palms, soles, and midline of the
back. The skin may have multiple nodules, papules, macules, and
ulcerations, or there may be diffuse cutaneous involvement with a
waxy, myxedema-like appearance.
• Similarly, the distribution of sensory loss is related to the local skin
temperature, the coolest parts such as the pinna of the ear; the tip of
the nose; malar areas of the face; dorsal surfaces of the hands,
forearms, and feet; and dorsolateral surfaces of the lower legs
being affected first. Because of the minimal inflamatory response,
nerve trunk involvement occurs late in this form.
• Commonly affected nerves include the ulnar, common peroneal,
and superficial branches of the facial and median nerves, in that
order.
• The selective involvement of small branches of the facial nerve
leads to the typical patchy nature of facial paralysis with early
weakness of medial forehead elevators.

Treatment
• Management consists of specific chemotherapy and prevention and
treatment of deformities.
• The current recommendation for paucibacillary infections (those
classified as indeterminate, tuberculoid, or borderline tuberculoid
Hansen’s disease) is the combination of dapsone, 100 mg/day, and
rifampin, 600 mg/day, for at least 6 months, followed by dapsone
monotherapy for 3 to 5 years.
• Patients with multibacillary infections (borderline or lepromatous
leprosy) receive the same combination therapy, with the addition of
clofazimine (50 mg/day). Treatment is continued for a minimum of
2 years or until skin smear results are negative.
• For dapsone-resistant strains or patients with glucose-6-phosphate
dehydrogenase deficiency, clofazimine and rifampin are used
together, with consideration of a third agent, either ofloxacin (400
mg/day), clarithromycin (250 mg twice a day), or minocycline (100
mg/day). The reactions need to be treated immediately with high
doses of corticosteroids.

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 Epilepsy

([Link] Alemam)
Definition

- It is a chronic disease characterized by recurrent stereotyped seizures

without provocation.
- A seizure is a transient disturbance of cerebral functions caused by
abnormal neuronal electrical discharge.
Prevalence

- It occurs in 0.4- 1% of the population.

- More common in the first decade of life and after the age of 65 years.

Pathogenesis

Epilepsy may be secondary to either:-

1-Abnormal neuronal membranes.
2- Imbalance between excitatory and inhibitory influences.

Etiology

1- Idiopathic: No apparent cause. It is secondary to an abnormality of

genes. This leads to abnormal neurotransmitter receptors.

2- Symptomatic: Secondary to brain pathology e.g trauma, tumor, etc .

Clinical Classification of Epilepsy

1- Generalized epilepsy :-

- Tonic - Clonic -
Tonic-Clonic
- Atonic - Myoclonic -
Absence
2- Partial epilepsy:-

- Simple partial.
- Complex partial.
112
 - Partial with secondary generalization.
3- Unclassified epilepsy.

Clinical Picture

The diagnosis of epilepsy is mainly clinical. The clinical presentation

depends on its type.

A- Generalized Epilepsy

1- Absence epilepsy
- Common in infancy and childhood (rare after age of 18 years old).
- It is usually idiopathic.
- Characterized by sudden brief attacks of loss of consciousness .

- No aura , convulsions, or post-ictal phenomena.

- There is stopping of motor activity but the postural functions of the

brain are preserved (i.e no falling).
- The attacks are frequent (may be 100 times/day) and each lasts for
5-15 seconds.

2- Generalized tonic-clonic epilepsy

Prodroma:-
- It occurs in some patients, few hours or a day before the fit, denoting
that the fit is expected .
- It may be: - Psychological (e.g depression or anxiety).
- Sensory (e.g headache).
- Motor (e.g myoclonic jerks).

The fit has 3 stages:-

Aura:-
- Present in 50% of patients.
- It is a symptom produced by the beginning of the discharge and points
to the site of the epileptic focus.
- It is too brief for the patient to save himself from falling comatose.

The convulsive stage:-

It starts with loss of consciousness and is divided into 2 phases:-
1- Tonic phase:- (½ minute)
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- Epileptic cry: due to the forcible expulsion of air through the partially
closed vocal cords.
- All voluntary muscles become rigid →
Head retraction and opisthotonus position.
U L:- Adduction and flexion. L.L:- Extension.
Respiratory muscles→ cyanosis.
- The powerful tonic spasm may lead to dislocation of joint (e.g shoulder)
or fracture of bone (e.g vertebra).

Clonic phase:- (1-2 minutes)

- The clonic jerks of the muscles → re-entry of air into the lung → ↓
cyanosis, and expired in short puffs mixed with saliva → mouth froth.
- Tongue or cheeks biting → staining the froth with blood.
- Emptying of the bladder, if it is full.
The post-convulsive stage (from few minutes to half an hour)
Flaccid coma → dilated pupils , lost corneal and tendon reflexes, and
extensor plantar reflex on both sides.
On awaking the patient may have :-
- Severe fatigue and go into deep sleep (or pass directly from coma to
sleep).
- Headache and vomiting.
- Post-epileptic automatism.

3- Myoclonic seizures

- Bilateral brief shock-like jerks of muscles for less than one second.

- The consciousness is preserved.

- More on awaking up or falling asleep.

B-Partial Seizures

1-Complex partial seizures

- Present in 40% of cases of epilepsy in adults.

- The central feature of complex partial seizure is impairment of
consciousness .
- It may or may not be preceded by symptoms and signs of simple partial

114
seizure.
- It may or may not be associated with automatisms.

2- Simple partial seizures

- They are caused by local cortical discharge (70% temporal,
20%frontal, and 10% others).

- Seizure symptoms depend on the site of epileptic focus, without

impairment of consciousness.

a. Motor signs.

- The most frequent type of simple partial

seizures.

- The convulsions affect mostly the face and

upper limb, but may spread to lower limbs.

b. somatasensory or special sensory symptoms

- It is rare, 2% of epileptic patients.

- It may be somatosensory as numbness, tingling,

needles or weak electric sensation

- It may be visual flashes or olfactory odors.

c- Autonomic.
e.g Recurrent sudden attacks of epigastric or abdominal pain
(most common type, and ascends to throat), flushing or
pallor, diaphoresis, vomiting, sphincters disturbances
d- Psychic: Abnormal attacks of unexplained fears or laughter
Investigations

Epilepsy is a clinical diagnosis.

1- EEG:

- The diagnosis of epilepsy is usually confirmed by EEG.

- The most specific epileptic discharges are spikes (or sharp

waves) and slow wave complexes.

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 - The first EEG is positive in only 50% of epileptic patients when
recorded in the interictal state. So , initial negative EEG does not
exclude epilepsy. Repeated EEG proves positive in about 90% of
cases.

2- MRI- Brain : for underlying structural lesions.

3- Laboratory:

- To exclude other causes of convulsions eg , metabolic,

toxic…….etc

- For monitoring the serum level of antiepileptic drugs.

Differential diagnosis of epilepsy

Epileptic seizures should be differentiated from other paroxysmal cerebral

dysfunctions e.g syncopal attacks, febrile convulsions , pseudoseizures.

Pseudoseizures:

- The attacks occur in front of others, to gain their attention

- No harm , no injury, no urine incontinence.

- No true loss of consciousness, no post-ictal confusion.

- EEG during the attack does not show epileptic dischrarge.

When to start TTT?

- The patient should have 2 fits to start medical treatment. The

interval between the 2 fits must be short (6-12months).
v - About ¾ of persons who have one seizure never have another.
- There are risk factors of recurrence of the second fit
- 2 or more factors : 100% chance of recurrence within 2 years. So,
patients with one fit plus 2 or more risk factors should be treated.

• Risk Factors (If there is single epileptic fit only) :

1- Positive family history.
2- Partial seizure type.
3- Post-ictal motor paralysis.
4- Abnormal EEG.
5- Evidence of structural lesion (strongest factor).
116
 General principles of TTT

1- Accurate diagnosis of epilepsy and its type e. g carbamazepine and

vigabatrine may exacerbate absence and myoclonic epilepsy.
2- Start with monotherapy as:
- It controls 70-90% of patients.
- Polytherapy → unnecessary side effects.
3- Start with the drug of first choice.

4- Start with minimum effective dose: if seizures persist, increase the

dose until the seizures are controlled or side effects appear.
5- If no side effects, the drug shouldn't be considered ineffective until the
plasma level of the drug documented that it reached the highest
therapeutic concentration.

Categories of AEDs

1- Brood-spectrum AEDs : e.g valproate, Benzocliazepines,

Barbiturates, lamotrigine, topiramate.
2- Against partial, CPS (± ± 2ry generalization) or primarily
generalized.
- e. g carbamazepeine, plenytoin, gabapentin, tiagabine

- These drug are not effective or even worsen other types of generalized
epilepsy e. g absence epilepsy and myoclonic epilepsy).

3- Others not fulfilling the criteria mentioned before: e. g

Etheusuximide: → Absence.

[Link] drugs of choice

a- Partial epilepsy: Carbamazepine.

b- Generalized tonic-clonic epilepsy (GTC):

Valproate: The most effective and broad spectrum
If GTC+ absence → valproarte is the first choice.
c- Absence epilepsy: Ethosuximide .
d- Unclassified epilepsy:
Brood spectrum AED e. g valproate, lamotrigine.

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Antiepileptic drug withdrawal
- After 2-3 years free of seizures on AEDs, discontinuation of TTT can be
made.
- About 80% of recurrence occurs in the first 4 months after stopping
TTT. So, dangerous activities should be avoided during this period.
- Withdrawal can be over 6 weeks or 9 months (but average is 2-3
months).

Status Epileptics

- Definition: 30 or more minutes (some consider it 5-10 min) of

continuous or recurrent seizures without recovery to baseline function.
- It is the most common neurological emergency and the mortality ranges
from 2-3% in children and 30% of adults
- Causes:
Any of the causes of acute symptomatic seizures.
Most common causes are (AED withdrawal – Fever).

Treatment
0 - 10 min
- Nasal o2 and insert airway if necessary.
- Take history and examine the patient.
- IV line to a) Draw blood sample for glucose, AEDs, renal, liver, ca and
Mg.
b) give 50 ml of 50% glucose + 100 mg thiamine (to avoid
wernick's encephalopathy).
10- 30 min
- Lorazepam 0.1 mg / kg or diazepam up to 20 mg + simultaneous
phenytoin 20 mg / kg (or phosphenytion) at a rate of 50 mg / min.
- Monitor ECG and B.P.

30-60 min
Additional 5 – 15 mg / kg fosphenytoin (20 mg / kg) with 50 mg / min.
At 60 min
Anaesthesia with Phenobarbital 5 – 15 mg / kg until epileptic activity is
clearly suppressed.

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 Table of anti-epileptic drugs:

Side Effects Dose Drug

Hepatotoxicity, pancreatitis, 15-60 mg/kg Valproate
tremors, weight gain and hair loss (Depakine)
Sedation, hypersensitivity, 15-25 Carbamazepine
hepatotoxicity, pancytopenia, (Tegretol)
hyponatremia
Hirsiutism, gingival hyperplasia, 3-7 mg/kg Phenytoin
coarse features of the face(lion face), (Epanutin)
ataxia
Sedation, dependence, tolerance 0.5-4 mg/d Clonazepam
(Rivotril)
Rash, tremors 5-10 mg/kg Lamotrrigine
(Lamictal)
Cognitive slowing, renal stones , 5-9 mg/kg Topiramate
loss of weight (Topamax)
Somnelence, asthenia, and 20-30 mg/kg Levitiracetam
behavioral changes (Keppra)

Epilepsy Surgery

About 5 – 10 % of cases of epilepsy benefits from surgery.

- Philosophy:-
Accurate localization of the site of onset of seizures and then
1- Curative TTT : Removal of the area of epileptogenic focus.
2- Palliative TTT: Disconnection of epileptogenic zone to prevent spread
of seizures.

- Timing:
If 3 AEDs fail to control epilepsy for 12 – 24 months, epilepsy surgery
should be considered immediately.

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 PARAPLEGIA
([Link] Alemam)
* Definition : Paraplgia is motor paralysis or paresis of both lower
limbs.

Approach to diagnosis of Paraplegia: *

1- Is it paraplegia?

2- Where is the lesion( UMN or LMN)?

3- What is the type of it (Focal, systemic or disseminated)?

* Exclude other causes of difficulty of walking:-

1- Painful conditions: e.g polyarthritis.

2- Ataxia : e.g cerebellar lesions.

3-Involuntary movements e.g advanced Parkinson disease or dystonia.

4- Mental retardation.

Causes of paraplegia:

1- Upper motor neuron lesion: (Spinal or cerebral).

2- Lower motor neuron lesion: ( AHCs , motor roots or peripheral
nerves).

Causes of cerebral paraplegia

A- Parasagittal region:

- Traumatic: e.g Depressed fracture of the skull or parasagittal subdural

hematoma.

-Inflammatory: e.g Encephalitis or meningo-encephalitis

- Vascular: e.g Superior sagittal sinus thrombosis

- Neoplastic: e.g Parasagittal meningioma.

B- Brain stem:
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 e.g Medline brainstem tumors or syringobulbia.

Causes of spinal paraplegia

A-Focal causes

- Compressive

-Vertebral: Fracture, disc prolapse, Pott s disease, tumors as hemangioma

or osteosarcoma or metastases.

-Meningeal: Exatr-adural e.g leukemic deposits or intra-dural e.g

neurofibroma.

- Cord (Intramedullary): e.g syringomyelia, glioma , or ependymoma.

2-Inflammatory: e.g transverse myelitis.

3- Vascular: e.g anterior spinal artery occlusion.

B- Systemic causes

- Heredofamilial : e.g hereditary spastic paraplegia , Friedriech ataxia.

Symptomatic: e.g subacute combined degeneration.-

Idiopathic: e.g motor neuron disease.-

C- Dissiminated causes

- Multiple sclerosis.

- Disseminated encephalomyelitis.

Clinical picture of focal spinal paraplegia

1- At the level of the lesion:

Localized pain, tenderness, or deformity (If the cause is vertebral).

Radicular manifestations: By affection of the posterior AND/OR

anterior roots.

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 2- Below the level of the lesion:

Motor manifestations :

Acute causes: Stage of flaccidity (due to neuronal shock) , then

stage of spasticity after 2-6 weeks.

Gradual causes: Paraplegia in extension then paraplegia in flexion.

Sensory Manifestations
If the cause is extra-medullary → Sensory level.
If the cause is intramedullary → Jacket sensory loss of dissociated
nature.

Sphincteric manifestations:
-Acute lesions →Retention of urine in the shock stage followed by
precipitancy of micturition.
-Gradual lesions → Precipitancy of micturition.

Causes of flaccid paraplegia

1- Polyradiculopathy.

2- Peripheral neuropathy : e.g GBS, porphyria.

3- NMJ disorders: e.g myasthenia gravis.

4- Muscle disease: e.g muscular dystrophy or acute polymyositis.

Transverse Myelitis

- It is an acute lesion involving the gray and white matter of a limited

number of the spinal cord segments.

- Causes:- viral infection, post-vaccination, demyelinating disease.

- Clinical Picture: Upper motor neurone paraplegia with sensory level

and sphincteric disturbances.

Investigations: MRI- spinal, CSF. -

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Anterior Spinal Artery Occlusion

- Cause: Thrombosis, embolism, or dissecting aortic aneurysm.

- Clinical Picture: As that of the transverse myelitis except the

sparing of the deep sensations, as the posterior column of the spinal
cord is supplied by the posterior spinal artery.

Syringomyelia

- It is a chronic disease characterized by gliosis and cavitation around

the central canal in the gray matter of the spinal cord.

Level: Commonly in the lower cervical and upper thoracic segments .-

- Clinical Picture: Motor: LMN weakness in the ULs, and UMNL in

the LLs.

Sensory: Jacket sensory loss of dissociated nature

Autonomic: Trophic ulcers in the fingers and

vasomotor changes.

Associated skeletal anomalies as pes cavus and

spina bifida.

Investigations: MRI-Spine-

Cauda Equina

It is a collection of lumbo-sacral roots in the lower part of the spinal

canal.

Causes of cauda equina lesions:

1- Congenital : Spina bifida

2- Traumatic: Disc prolapse or vertebral fracture

3- Inflammatory: Pott disease.

4- degenerative : Lumbar spondylosis.

5- Neoplastic: Meningioma, metastases.

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Clinical Picture:

1- Motor : LMN weakness affecting one or both lower limbs. The

weakness is in the muscles supplied by the affected root.

2- Sensory: Painful onset, with radicular parasthesia at onset followed by

hypothesia later.

3- Sphincteric disturbances: Late

Invetigations: MRI-Lumbosacral spine.

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 COMA
([Link] Said)

Definition:
It is a prolonged state of unconsciousness ( lasting more than six hours) , in which a person:
cannot be awakened; fails to respond normally to painful stimuli, light, or sound; lacks a
normal sleep-wake cycle; and, does not initiate voluntary actions.

DD from stupor:

Stupor is unresponsiveness from which a person can be aroused only by vigorous physical
stimulation. Coma is unresponsiveness from which a person cannot be aroused.

Pathophysiology:

For a person to maintain consciousness, two important neurological components must

function:

1- Cerebral cortex—the gray matter that covers the outer layer of the brain.

2- Reticular activating system (RAS).

• RAS is a more primitive structure in the brainstem that is tightly in connection with
reticular formation (RF).

• The RAS area of the brain has two tracts, the ascending and descending tract.

• Made up of a system of acetylcholine-producing neurons, the ascending track, or

ascending reticular activating system (ARAS), works to arouse and wake up the
brain, from the RF, through the thalamus, and then finally to the cerebral cortex.

• Injury to either or both of these components is sufficient to cause a patient to

experience a coma.

Classification:

Glasgow Coma Scale:

• It is a neurological scale that aims to give a reliable, objective way of recording the
conscious state of a person for initial as well as subsequent assessment.

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 • A patient is assessed against the criteria of the scale, and the resulting points give a
patient score between 3 (indicating deep unconsciousness) and either 14 (original
scale) or 15 (the more widely used modified or revised scale).

• GCS was initially used to assess level of consciousness after head injury, and the
scale is now used by first aid, nurses and doctors as being applicable to all acute
medical and trauma patients.

• In hospitals it is also used in monitoring chronic patients in intensive care.

• The scale is composed of three tests: eye, verbal and motor responses. The three
values separately as well as their sum are considered. The lowest possible GCS is 3
(deep coma or death), while the highest is 15 (fully awake person).

2 3 4 5 6
Does not open eyes Opens eyes in Opens eyes in Opens eyes spontaneously
response to painful response to
stimuli voice

Makes no sounds Incomprehensible Utters Confused, Oriented,

sounds inappropriate disoriented converses
words normally
Makes no movement Extension to painful Abnormal Flexion / Localizes Obeys
stimuli (decerebrate flexion to Withdrawal to painful commands
response) painful stimuli painful stimuli stimuli
(decorticate
response)

Generally, brain injury is classified as:

• Severe, with GCS < 8-9

• Moderate, GCS 8 or 9–12 (controversial)
• Minor, GCS ≥ 13.

• Periods of impaired consciousness can be short or long.

• The degree of impairment can range from slight to severe:
• Lethargy is a slight reduction in alertness or mild mental fogginess (clouding of
consciousness). People tend to be less aware of what is happening around them and to
think more slowly.

• Obtundation refers to a moderate reduction in alertness or moderate clouding of

consciousness.

• Altered mental status is sometimes used by doctors to refer to a change in

consciousness, such as lethargy, obtundation, or delirium.

126
 • Stupor is an excessively long or deep state of unresponsiveness.

A person can be aroused from it only briefly by vigorous stimulation, such as repeated
shaking, loud calling, or pinching.

• Coma is a state of complete unresponsiveness. A person cannot be aroused at all. A

person in a deep coma lacks the most basic responses, such as moving a limb away from
something that hurts. People may still have reflexes (such as the knee jerk reflex), which
are automatic responses to a stimulus and which do not involve the brain

Causes of coma:

• Traumatic brain injuries: often caused by traffic collisions or acts of violence, are
common causes of comas.

• Stroke: Reduced or interrupted blood supply to the brain (stroke), which may be
caused by blocked arteries or a burst blood vessel, can result in coma.

• Tumors: Tumors in the brain or brainstem can cause coma.

• Diabetes: blood sugar levels that become too high (hyperglycemia) or too low
(hypoglycemia) can cause a stroke or coma.

• Lack of oxygen: People who have been rescued from drowning or those who have
been resuscitated after a heart attack may not awaken due to lack of oxygen to the
brain.

• Infections: as encephalitis and meningitis cause swelling (inflammation) of the brain,

spinal cord or the tissues that surround the brain. Severe cases of these infections can
result in brain damage or coma.

• Seizures: Ongoing seizures may lead to coma.

• Toxins: Exposure to toxins, such as carbon monoxide or lead, can cause brain
damage and coma.

• Drugs and alcohol: Overdosing of drugs or alcohol can result in coma.

• Metabolic disorders: hyponatraemia or hypernatraemia and hypothermia or

hyperthermia.

• Endocrine disorders :as hypothyroidism

• Other causes:

• Cardiac arrest.

127
 • Heart or lung disorders( if severe):as severe heart failure , chronic obstructive
pulmonary disease, pulmonary edema, pulmonary embolism, and severe and
long-lasting asthma attacks.

• Liver and Renal failure.

Diagnosis of coma:

• Diagnosis of coma is simple, but diagnosing the cause of the underlying disease
process is often challenging.
• The first priority in treatment of a comatose patient is stabilization following the basic
ABCs (standing for airway, breathing, and circulation).
• Once a person in a coma is stable, investigations are performed to assess the
underlying cause.
• Investigative methods are divided into physical examination findings and imaging
(such as CAT scan, MRI, etc.) and special studies (EEG, etc.)

Clinical presentation:

Symptoms:

1) Consciousness is impaired to varying degrees. People in a stupor are usually

unconscious but can be aroused with vigorous stimulation. People in a coma are
unconscious and cannot be aroused
2) The pattern of breathing is usually abnormal. People may breathe too rapidly, too
slowly, too deeply, or irregularly. Or they may alternate between these abnormal
patterns.
3) Muscles may remain contracted in unusual positions. For example, decerebrate
rigidity, decorticate rigidity or the entire body may be limp. Sometimes muscles
contract sporadically or involuntarily.
4) pupils: one or both may be widened (dilated) and not react to changes in light. Or the
pupils may be tiny. The eyes may not move or may move in abnormal ways.
5) The disorder that is impairing consciousness may cause other symptoms. For
example, if the cause is meningitis (infection of the fluid-filled space within the
layers of tissue covering the brain and spinal cord), symptoms may include fever,
vomiting, headache, and a painful, stiff neck that makes lowering the chin to the chest
difficult or impossible.

128

Initial assessment and evaluation:

1) Detection and treatment of any immediate life threatening condition:(as hemorrhage,

airway obstruction, hypotension or arrhythmia)
2) 50% dextrose is given intravenous immediately without waiting for blood glucose
level determination. Thiamine is given with the glucose to prevent Wernicke-
Korsakoff syndrome
3) Assessment of the level of consciousness
4) Assessment of the risk of asphyxia

In those with deep unconsciousness, there is a risk of asphyxia as the control over the
muscles in the face and throat is diminished. As a result, those presenting to a hospital with
coma are typically assessed for this risk. If the risk of asphyxiation is deemed high, doctors
may use various devices (such as an oropharyngeal airway, nasopharyngeal
airway or endotracheal tube) to safeguard the airway.
5) Physical examination :

General examination:

1) Examination of skin, nails and mucous membranes(cyanosis, pallor, cherry redness

,petechiae, jundice, uraemic frost, hypo or hyperpigmentation, signs of trauma)
2) Examination of breath: (acetone or alcohol)
3) Examination of fundi: (papilloedema, hypertensive or diabetic retinopathy, Roth spots,
subhyaloid hemorrhage)

4) Examination of the head, face, and skin for clues to the cause, such as the following:
 Black eyes, cuts, bruises, or leakage of cerebrospinal fluid (fluid that surrounds the
brain) from the nose or ears suggests a head injury.
 Needle marks suggest an overdose of a drug, such as heroin.
 Rashes often suggest an infection, such as sepsis (a severe blood infection) or a brain
infection.
 If people have bitten their tongue, seizures may be the cause.

5) Vital signs:

 Temperature (rectal is most accurate): Abnormally high temperature may indicate

infection, heatstroke, or an overdose of a drug that stimulates the body (such as
cocaine or an amphetamine).
 Abnormally low temperature may indicate prolonged exposure to cold, an
hypothyroidism, alcohol intoxication, a sedative overdose or, in older people,
infection.
 Blood pressure, heart rate (pulse), respiratory rate, and oxygen saturation. They
should be evaluated quickly to gain insight into a patient's metabolism, fluid status,
heart function, vascular integrity, and tissue oxygenation.
 Respiratory pattern (breathing rhythm):it is significant and should be noted in a
comatose patient. Certain stereotypical patterns of breathing have been identified
including :

129
  Cheyne-Stokes breathing is a form of breathing in which the patient's
breathing pattern is described as alternating episodes of
hyperventilation and apnea. This is a dangerous pattern and is often seen in
pending herniations, extensive cortical lesions, or brainstem damage.

Apneustic breathing: sudden pauses of inspiration and is due to a lesion of
the pons.
 Ataxic breathing is irregular and is due to a lesion (damage) of the medulla.

6) Urinary or fecal incontinence may signify an unwitnessed seizure.

7) Scalp is palpated for signs of trauma
8) Ears and nose examination: for blood or cerebrospinal fluid.
9) Neck examination: resistance for passive neck flexion suggests meningitis or
subarachnoid hemorrhage.
10) Neurological examination:

Motor responses:

• Inspection of limb position and spontaneous movements.(voluntary or

involuntary as seizures or myoclonus) .

• Asymmetric movements or postures can indicate either hemiparesis or

focal seizures.

• Asymmetry of muscle tone suggests a structural lesion, but may not be

clear which side is abnormal.

• Assessment of posture and body habitus .There are often two

stereotypical postures seen in comatose patients.

• Decorticate posturing is a stereotypical posturing in which the patient

has arms flexed at the elbow, and arms adducted toward the body, with
both legs extended. it indicates a lesion (a point of damage) at or above
the red nucleus.

• Decerebrate posturing is a stereotypical posturing in which the legs are

similarly extended (stretched), but the arms are also stretched (extended at
the elbow). It indicates a lesion at or below the red nucleus. In other
words, a decorticate lesion is closer to the cortex, as opposed to a
decerebrate cortex that is closer to the brainstem.

130

Pupil assessment: It is often a critical portion of a comatose examination, as it can
give information as to the cause of the coma.

Possible interpretation
Normal eye with two pupils equal in size and reactive to light. This means that the patient is
•
probably not in a coma and is probably lethargic, under influence of a drug, or sleeping.

"Pinpoint" pupils indicate heroin or opiate overdose, and can be responsible for a patient's
coma. The pinpoint pupils are still reactive to light, bilaterally (in both eyes, not just one). •
Another possibility is the damage of the pons.

One pupil is dilated and unreactive, while the other is normal (in this case the R eye is
dilated but the L eye is normal in size). This could mean a damage to the oculomotor •
nerve ( CN III) on the right side, or possibility of vascular involvement.

Both pupils are dilated and unreactive to light. This could be due to overdose of certain
•
medications, hypothermia or severe anoxia (lack of oxygen).

Eye movements:

 Abnormal eye movements may be conjugate or dysconjugate

 Eyes deviated conjugately away from the hemiparetic side: indicates destructive
cerebral lesion on the side towards which the eyes are directed.
 Eyes deviated conjugately towards the hemiparetic side :it favors pontine lesion or
adversive seizures.
 Eyes roving from side to side with slow smooth velocity: indicates non wakefulness
and an intact brainstem.
 Jerky movements suggests saccades and relative wakefulness.
 Downward eye deviation suggests a lesion of the rostral midbrain or thalamus. it may
be accompanied by loss of pupillary light reactivity.(perinaud syndrome).
 Vertical divergence of the eyes (skew deviation):in brainstem or cerebellar lesions.
 Ocular bobbing: conjugate brisk downward eye movements several times per minute
.it usually reflects lesion of the pons.
 Periodic alternating or ping pong gaze: rapid regular conjugate side to side
horizontal movements indicate extensive cerebral or cerebellar lesions with intact
brainstem.
 If eye movements are unilaterally or bilaterally limited ,then oculocephalic or caloric
test is performed.

 Oculocephalic reflex ( the doll's eye).

131
Method: It is performed to assess the integrity of the brainstem. Patient's eyelids are gently
elevated and the cornea is visualized. The patient's head is then moved to the patient's left, to
observe if the eyes stay or deviate toward the patient's right; same maneuver is attempted on
the opposite side. If the patient's eyes move in a direction opposite to the direction of the
rotation of the head, then the patient is said to have an intact brainstem. However, failure of
both eyes to move to one side, can indicate damage or destruction of the affected side. In
special cases, where only one eye deviates and the other does not, this often indicates a lesion
(or damage) of the medial longitudinal fasciculus (MLF), which is a brainstem nerve tract.

Caloric reflex test also evaluates both cortical and brainstem function; Method: cold water is
injected into one ear and the patient is observed for eye movement; if the patient's eyes slowly
deviate toward the ear where the water was injected, then the brainstem is intact, however
failure to deviate toward the injected ear indicates damage of the brainstem on that side.
Cortex is responsible for a rapid nystagmus away from this deviated position and is often seen
in patients who are conscious or merely lethargic.

Assessment of cranial nerves :

• Due to the unconscious status of the patient, only a limited number of the
nerves can be assessed. These include CN II,CN III, CN V, CN VII and CN IX,
CN X.
• Gag reflex helps assess cranial nerves 9 and 10.
• Pupil reaction to light is important because it shows an intact retina, and CN
II; if pupils are reactive to light, then that also indicates that the CN III (or at
least its parasympathetic fibers) are intact.
• Corneal reflex assess the integrity of cranial nerves VII and V. Cranial nerve
V and its ophthalmic branch (V1) are responsible for the afferent arm of the
reflex, and the cranial nerve VII is responsible for the efferent arm, causing
contraction of the muscle orbicularis oculi resulting in closing of the eyes.

Investigations:

a) Laboratory tests:

 Blood levels of sugar, sodium, calcium, alcohol, oxygen, and carbon dioxide.
 Complete blood count: Red and white blood cell counts are determined.
 liver function tests.
 Kidney function tests.

132
  Blood and urine analysis: to determine whether any commonly used or suspected
toxic substances are present.
 Arterial blood gases: oxygen level in blood with a sensor placed on a finger (called
pulse oximetry). They also measure levels of oxygen, carbon dioxide, and sometimes
other gases in a sample of blood withdrawn from an artery (arterial blood gas tests).
These tests are done to check for heart and lung disorders and for possible carbon
monoxide poisoning.
 Blood and CSF cultures.
b) Electroencephalogram:(EEG):
 mainly to identify nonconvulsive seizure.
 it can distinguish coma from psychic unresponsiveness or locked in syndromes.
c) Computerized tomography(CT) or Magnetic resonance imaging(MRI):

 It is performed promptly in patients with unexplained coma.

 Computerized tomography (CT scan). CT scan can show a brain hemorrhage, tumors,
strokes and other conditions. This test is often used to diagnose and determine the
cause of coma.

 Magnetic resonance imaging (MRI). An MRI can detect brain tissue damaged by an
ischemic stroke, brain hemorrhages and other conditions. MRI scans are particularly
useful for examining the brainstem and deep brain structures.

d) Spinal tap (lumbar puncture) :

 Can check for signs of infections in the nervous system.

 CT or MRI of the head is often done before the spinal tap to determine whether
pressure inside the skull is increased—for example, by a tumor or bleeding within the
brain (intracerebral hemorrhage). If pressure is increased, a spinal tap could make the
brain shift downward by rapidly reducing the pressure below the brain and thus, at
least theoretically, cause or worsen brain herniation.

133

Treatment:
• Medical treatment:

1) Admission in ICU.
2) Stabilization of the patient: The first steps in treatment, sometimes done by
emergency medical personnel, are to check whether the airway is open, whether
breathing is adequate, and whether pulse, blood pressure, and heart rate are normal
(to make sure blood is reaching the brain).

• If possible, any problems present are corrected by using intubation and ventilation,
administration of intravenous fluids or blood and other supportive care as needed.

3) Maintaining the health of patient’s physical state.

• Prevention of infections such as pneumonias, bedsores (decubitus ulcers), and

providing balanced nutrition.
• These infections may appear from the patient not being able to move around, and
being confined to the bed.
• The nursing staff moves the patient every 2–3 hours from side to side and depending
on the state of consciousness sometimes to a chair. The goal is to move the patient as
much as possible to try to avoid bedsores, atelectasis and pneumonia.

Pneumonia can occur from the person’s inability to swallow leading to aspiration, lack of
gag reflex or from feeding tube, (aspiration pneumonia).

4) Comatozed patients may become restless so, special care is needed to prevent them
from hurting themselves. Patients who are restless may also try to pull on tubes or
dressings so soft cloth wrist restraints may be put on. Side rails on the bed should be
kept up to prevent the patient from falling.
5) Treatment of the cause:

 Low blood sugar level, glucose (a sugar) is immediately given intravenously. Giving
glucose often results in instant recovery if the coma is caused by a low blood sugar
level. Thiamin is always given with glucose because if people are undernourished
(usually because of alcohol abuse), glucose alone can trigger or worsen a brain
disorder called Wernicke encephalopathy .
 If opioid toxication is suspected, the antidote naloxone may be given

134
 If the cause is a head injury, the neck must be immobilized until doctors can check
for damage to the spine. People in a deep stupor or a coma after a head injury
sometimes benefit from treatment with amantadine
 Rarely, when doctors suspect that certain toxic substances have been ingested within
about 1 hour, they may insert a large tube through the mouth and into the stomach so
that the stomach can be pumped. Pumping the stomach is done to identify its contents
and to prevent more of the substances from being absorbed. Activated charcoal may
also be given through the tube or through a smaller tube inserted through the nose
(nasogastric tube). The charcoal prevents the stomach from absorbing more of the
substances
 If findings suggest that the pressure within the skull is increased, particularly if
doctors suspect brain herniation, doctors may drill a small hole in the skull and insert
a pressure-monitoring device into one of the fluid-filled spaces (ventricles) in the
brain.
 If the pressure is increased, the following measures may be taken to lower it:
a) The head of the bed may be elevated.

b) Diuretics or other drugs may be used to reduce fluids in the brain and rest of the
body.

c) A sedative may be given to control excess involuntary muscle contractions, which

can increase pressure within the skull.

d) Blood pressure is sometimes lowered, particularly if it was already high.

e) If other measures do not work, the skull may be opened surgically, creating more
room for the swollen brain and thus reducing pressure on the brain.

 If the cause is a brain tumor or abscess, corticosteroids, such as dexamethasone, may

help reduce pressure. However, corticosteroids are not used when increased pressure
is caused by certain other disorders, such as intracerebral hemorrhage or a stroke,
because corticosteroids may make these conditions worse.
6) Attempt to wake comatose patients:
Some hospitals treat their patients by either reversing the cause of comatose (i.e.,
glucose shock if low sugar), giving medication to stop brain swelling, or inducing
hypothermia. Inducing hypothermia on comatose patients provides one of the main
treatments for patients after suffering from cardiac arrest. In this treatment, medical
personnel expose patients to “external or intravascular cooling” at 32-34 °C for 24
h.; this treatment cools patients down about 2-3 °C less than normal body
temperature.

135

Long-term care:
1) Care of feeding:

By a tube inserted through the nose and into the stomach. Sometimes they are fed
through a tube (called a percutaneous endoscopic gastrostomy tube, or PEG tube)
inserted directly into the stomach through an incision in the abdomen. rugs may also
be given through this tube

2) Care of eyes: eye drops can help.(for eye dryness).

3) If people are incontinent, care should be taken to keep the skin clean and dry. If the
bladder is not functioning and urine is being retained, a tube (catheter) may be placed
in the bladder to drain urine.
4) Physical therapy may also be used to prevent contractures and orthopedic deformities
that would limit recovery for those patients who emerge from coma.

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 CNS Infections

([Link] Hatem)

Central nervous system (CNS) infections are suggested by a constellation of signs,

symptoms, and laboratory studies. The major groups of CNS infections include:

• Bacterial meningitis.
• Viral meningitis.
• Chronic meningitis.
• Acute encephalitis.
• Brain abscess.

HISTORY
The diagnosis of meningitis (inflammation of the meninges) is suggested when
history includes fever, headache, and stiff neck.

• Acute bacterial meningitis :

- is a neurologic emergency, with symptoms developing over hours or
days.
- Cerebrospinal fluid (CSF) studies show a neutrophilic pleocytosis, low
glucose compared with blood glucose, and high protein.
- Cultures or bacterial antigens are positive.
- CSF pressure may be high.
- Delay in diagnosis and treatment can lead to permanent injury or death.
• Viral meningitis :
- is suggested by the constellation of fever, headache, and stiff neck-
- the cerebrospinal fluid (CSF) features include a lymphocytic
pleocytosis, normal sugar, and negative culture for bacteria.
• Chronic meningitis :

- has a more indolent presentation,

- may be associated with cranial nerve palsies, cognitive changes, or

stroke-like events.

• The diagnosis of encephalitis (evidence of brain parenchymal involvement)

is suggested when:

- the history includes fever,

- the acute onset of mental status changes (ranging from confusion to
coma),
- seizures, and
- focal neurologic signs such as paralysis, acute psychosis, or aphasia.
- CSF shows a lymphocytic pleocytosis with normal sugar.

137
 - PCR for herpes simplex or other viral causes of encephalitis may be
positive.
- MRI may show abnormalities in certain parts of the brain, such as the
temporal lobe depending on the type of encephalitis.

• The diagnosis of brain abscess is suggested by:

- subacute fever,
- headache,
- focal signs or
- seizures,
- signs of increased intracranial pressures.
- Fever is seen in approximately 50% of adults and up to 80% of
children with brain abscess.
- Imaging shows a focal ring enhancing mass lesion or multiple lesions.
- CSF studies should not be performed to avoid herniation due to mass
effect.

Pursue the Following Points in the History:

• Has there been a recent respiratory or gastrointestinal infection?
• Has the patient had a recent infectious illness that may progress to meningitis
(e.g., otitis media leading to pneumococcal meningitis)?
• Has the patient had a positive reaction to purified protein derivative, or known
exposure to tuberculosis?
• Has the patient been exposed to others with infectious illness (e.g.,
meningococcus or Haemophilus influenzae)?
• Has there been recent travel to another state (e.g., exposure to mosquitoes
causing arbovirus-associated encephalitis), or another country (cysticercosis in
Central America)?
• Has there been a subtle personality change and low-grade fever (e.g., in
chronic meningitis such as Cryptococcus)?
• What is the patient's occupation (e.g., painter exposed to Cryptococcus in
pigeon droppings)?
• Does an underlying disease predispose the patient to CNS infection?
o Lymphoma, leukemia.
o Other malignancy.
o Renal failure.
o HIV/AIDS, other immunodeficiency states.
o Alcoholism.
o Diabetes.
o Post-transplant patient.
o Asplenic (functional or surgical).
• Is the patient receiving a drug(s) that predisposes to infection?
o Chemotherapy.
o Immunosuppressant or immunomodulator.
o Corticosteroids.

138
 • Has the patient had a recent illness such as mumps, or chickenpox that may be
followed by meningitis or meningoencephalitis?

• Is the patient bacteremic, or has the patient recently been bacteremic? This
increases the chances of secondary CNS infection.
• Has there been a recent head injury?
• Has there been a recent neurosurgical procedure or penetrating skull trauma?
• Has there been a recent insect bite leading to Lyme disease, or rickettsial
infection, which mimics bacterial meningitis?

PHYSICAL AND NEUROLOGIC EXAMINATION

• Check vital signs. Temperature may be higher in bacterial than in viral CNS
infection. Herpes simplex encephalitis often results in a high fever (104°F-
105°F). Tachycardia is seen in bacterial and viral CNS infection.
• Check eardrums; examine sinuses for tenderness.
• Check for stiff neck. Look for Kernig sign (with thigh flexed on abdomen,
patient resists knee extension), or Brudzinski sign (attempt to flex the neck,
results in reflex flexion of the knee and hip). Remember that the elderly,
infants, and immunosuppressed patients may have meningitis without
prominent meningeal signs. Comatose patients may not have meningismus.
• Look for stigmata of chronic liver disease, and chronic lung disease as a
predisposing factor for CNS infection.
• Look for peripheral signs of embolization in a patient suspected of having
subacute bacterial endocarditis or staphylococcal septicemia.
• Examine the heart carefully (e.g., changing murmur in subacute bacterial
endocarditis with valvular disease as source of septic embolism).
• Examine for lymph-node enlargement or splenomegaly. These signs may
suggest a lymphoproliferative disorder, in which CNS infections commonly
are seen.
• Is there evidence of CSF rhinorrhea caused by a defect or fracture in the
cribriform plate?
• Examine for petechial or purpuric lesions caused by meningococcemia, or
staphylococcal bacteremia.

LABORATORY
• All patients suspected of having meningitis should have a lumbar puncture
(LP), and treatment with antibiotics as soon as possible
• . Record the opening pressure. If focal neurologic symptoms or signs are
present and brain abscess is a consideration, obtain a contrast-enhanced
computed tomography (CT) or magnetic resonance imaging (MRI) scan first,
but do not allow significant delay when there is a high likelihood of
meningitis. If meningitis is a reasonable possibility and imaging is necessary,
it may be appropriate to give IV antibiotics immediately. Blood cultures
should be drawn before antibiotics are begun. See Chapter 30 for a discussion
of CSF examination.

In addition, note the following points regarding meningitis and encephalitis:

139
 o CSF pressure is usually moderately elevated in bacterial meningitis
(200 to 300 mm H2O), and mildly elevated in viral meningitis or
encephalitis.
o Cell count in untreated bacterial meningitis may range from 100 to
10,000/mm3 with a predominance of neutrophils; the fluid is usually
cloudy. In viral meningitis, cell counts of 10 to 1,000/mm3 with a
predominance of mononuclear cells are expected.
o CSF glucose is usually less than 40 mg/dL in bacterial or tuberculous
meningitis (or less than 60% of simultaneously obtained blood
glucose), whereas it is usually normal, or only modestly reduced in
viral meningitis or encephalitis.
o CSF protein is usually higher than 100 mg/dL in bacterial meningitis,
whereas a mild elevation (50-100 mg/dL) is expected in viral
meningitis or encephalitis. A mild elevation also may be encountered
in partially treated meningitis.
o Elevated CSF lactate levels are commonly encountered in patients with
meningitis following neurosurgical procedures.

Gram stain usually detects the causative organism in bacterial meningitis.

India ink stain is helpful in diagnosing cryptococcal meningitis, as are CSF
and serum cryptococcal antigens. Bacterial antigens can be detected in the
spinal fluid by a variety of special techniques and may be helpful if the
patient received antibiotic therapy before the LP.

• Routine laboratory tests may offer clues. The white blood cell count is usually
markedly elevated in bacterial meningitis and mildly elevated or normal in
viral meningitis.
• Check for hyponatremia, caused by inappropriate antidiuretic hormone
secretion, as a complicating feature in a meningitis patient with increasing
lethargy.
• Chest radiograph may demonstrate a source of CNS infection (e.g., pneumonia
or bronchiectasis).
• The electroencephalogram (EEG) may be normal or slightly slow in
meningitis and encephalitis, but it often shows focal features in brain abscess
and paroxysmal features in the temporal lobe in herpes simplex encephalitis.
• CT and MRI scans are usually normal in uncomplicated meningitis, but are
often focally abnormal in herpes simplex encephalitis (temporal lobe). They
may demonstrate complications of meningitis such as subdural fluid
collections, hydrocephalus, or cerebral infarction.
• In patients with suspected viral CNS infections, obtain a serum specimen
acutely, and save to compare with convalescent sera for an increase in
antibody titers (e.g., in mumps infection).
• In suspected enterovirus CNS infection (Coxsackie, Echo), the virus often is
detected in stool specimens. Mumps virus may be isolated from saliva, throat
washings, or CSF.
• Bacteremia is present in many patients with bacterial meningitis and should be
detected by appropriate blood cultures.
• Beware of coagulopathy in patients with fulminant meningitis (especially
meningococcus).
• Use PCR (polymerase chain reaction) to identify herpes simplex.

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 • TREATMENT
1)Bacterial Meningitis
• The mainstay of treatment of bacterial meningitis is intravenous antibiotics .
• For suspected undiagnosed bacterial meningitis in adults, start ceftriaxone 2 g
intravenously (IV) every 12 hours.
• If penicillin-resistant pneumococcus is a concern, vancomycin 1 g IV every 12
hours should be administered, until susceptibilities are available.
• If Listeria is a consideration (immunosuppressed individual), ampicillin 2 g
IV, every 4 hours should be added to the regimen.
• Appropriate dosing modifications for age and renal function need to be
considered for all patients.
• For those with a severe allergy to beta-lactam antibiotics, chloramphenicol
may be prescribed.
• Remember, if a lumbar puncture is delayed for any reason, consider giving
empiric antibiotics before LP.
• Early treatment is crucial in these patients.

Other measures include the following:

• Seizures are common in meningitis, and usually are treated with intravenous
phenytoin or fos-phenytoin.
• Fluid restriction to 1,200 to 1,500 mL/day may be needed to reduce brain
swelling, or to control the syndrome of inappropriate antidiuretic hormone.
• Early use of dexamethasone 0.15 mg/kg IV every 6 hours for 2 days in
children, and dexamethasone 10 mg IV q6h for 4 days in adults, may reduce
unfavorable outcomes in adults and children with bacterial meningitis.
• Standard infection-control precautions (gloves, hand-washing, face/eye/mouth
shield) and additional droplet precautions are essential for all cases of known
or suspected meningitis.
• Family members, medical personnel, and others with close contact to patients
with meningococcal meningitis should receive prophylaxis with one of the
following regimens:
o Ciprofloxacin 500-mg single oral dose (adults only).
o Rifampin 600 mg orally every 12 hours for 2 days.
o Ceftriaxone 250 mg intramuscularly (adult dosing; check for
appropriate pediatric dosing).

2)Viral Meningitis/Encephalitis
• Treatment of viral meningitis is supportive.
• In cases of nonherpetic viral encephalitis, treatment is also supportive, and
directed at possible complications.
• For herpes simplex encephalitis, acyclovir has greatly improved morbidity
and mortality. Usual dosage is 10 mg/kg every 8 hours IV, with vigorous
hydration to avoid nephrotoxicity.
• Take meticulous care to promptly and completely dispose of needles and
syringes, and precautions should be undertaken in handling stool specimens in
those with enteroviral infection.
• Isolate patients suspected of having measles, chickenpox, or rubella.
141
 • Treat fever with acetaminophen or aspirin. A cooling blanket may be helpful
for extreme hyperthermia.
• Treat seizures that accompany encephalitis.

3) CHRONIC MENINGITIS
Chronic meningitis presents with variable signs of meningeal irritation, cranial nerve
dysfunction, and focal or global CNS dysfunction lasting 4 weeks or more. There is
CSF pleocytosis, which may be caused by infectious or noninfectious processes (e.g.,
tuberculosis, fungus, hypersensitivity reaction, CNS tumor, chronic HIV, syphilis, and
sarcoidosis). Treatment depends on the specific etiology.

4) BRAIN ABSCESS
If brain abscess is a consideration, avoid lumbar puncture until mass lesion has been
excluded by CT or MRI. Aspiration or excision of brain abscesses, with appropriate
antibiotic coverage and steroid therapy for edema, is the usual treatment. More
conservative management of small abscesses with empiric antibiotics and close
radiological follow-up is being used.

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 Muscle Diseases (Myopathies)

[Link] Elkapany
Definition:

Are diseases affecting voluntary muscles

Classifications:

Inherted

a. Muscular dystrophies.

b. Myotonic dystrophy.

c. Congenital myopathy.

d. Primary metabolic myopathy.

e. Congenital myasthenic syndrome.

f. Channelopathies.

Acquired

a. Inflammatory myopathy.

b. Drug and toxin induced.

c. Endocrinal.

d. Secondary metabolic.

e. Paraneoplastic.

f. Myasthenia Gravis and Eaton Lombert.

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Clinical presentations:

1. Wealcness:

• Most important.

• Bilateral, symmetacil iproxima;.

2. Muscle wasting or hypertrophy in some cases.

3. Fatigre and exercise intolerance.

4. Pain: either focalized due to trauma or ischemia or generalized due to

inflammation or drug induced.

5. Muscle cramps.

6. Myoglobinuria passage of dolce urine due to extensine muscle damage.

Investigations:

1. serum enzymes: creatine kinase level is elevated.

2. EMG:- (electromyography)

• amplitude and duration of motor unit potentials with polyphasicity.

• complete interference pattern.

3. Muscle biobsy.

4. Molecular genetic studies.

144
 Muscular dystrophies

Def:

Are primary inherted degenerative progressive disorders of muscle.

The main site of pathology is muscle fiber membrare.

Classification:

Autosomal-Recessiue Autosomal – dominant Linked

Limb girdle congenital Fascioscopubumeral Duchene becker

ditaltype. oculopharyngeal

Distal myopathy
limbgirdle (uncommon)

Duchene muscular dystrophy

• X- linked affect boys

• Age of onset: first decade of life.

(usually at age of walky, sometimes can lead to delayed walky)

• Clinical picture:

1. Weakness:

• start in pelvic girdle muscles.

• Lead to difficulty in climbing stairs.

• Child raises from floor in a characteristic fashion(Gower's)

waddling gait.

• Shoulder girdle affection within 2-3y.

• Ambulation is lost at about 10 years.

2. Muscle hypertrophy:

145
 • In early stage.

• Most evident in calfmuscles quadriceps muscle.

3. Exaggerated lumbor lordosis prootuderant abdomen.

4. spinal deformity and contractures.

5. Respiratory muscle weaknes recusant chest infections.

6. cardiac involvement charactenistic EGC changes (tall rwaves right pericardial leads
narrow Q waves in lelt pericardial leads)

7. Delayed speech, low IQ.

Management:-

• Steroids in low dose slows progression of the disease.

• Gene therapy.

• Regular physical exercise.

• Splinting and walking aids.

• Spinal orthosis.

• Occupational therapy.

• Dietary advice to avoid obesity.

• Assisted verntillation if Reap n. Affection.

Becker Muscular dystrophy

Benign type:

Age: second – to third decade of life.

C/ P:-

• Weakness in pelvic girdle and shoulder girdle.

• Exercise induced muscle cramps and calf hypertrophy(early)

146
 • No cardiac involvement, rontracture or deformity.

Limb girdle muscular dystrophy

Age: 2nd to third decade.

Both sex.

C/P:

• Either shoulder girdle addiction first in soy.

• More benign from.

• Pelvic girdle start first.

• Contractures and skeletal deformities are late.

147
 Fascia scapula humeral

AD.

Age: Second decade of life.

C/P:

• weaknes involue facial muscles.

• Shoulder girdle.

• Anterior tibial muscle.

• Abortive cases occus.

Oculopharynged muscular dystrophy

Age: 5th-6th decade.

C/ P:

• Ptosis.

• Dysphasia.

• Facial weakness.

• Limb girdle- Late.

148
 Distal type of myopathy

Age: 40-60tears.

Sex: male more.

C/P:

• Weakness of small muscles of hand.

• Anterior t. bial muscles.

Myotonic dystrophy

• AD

• Age on onset : adolescence

• Sex : make more

• CIP

a) – weakness and wasting of : * Facial muscles and muscles of

mastication

* slernomastoid muscle

* in the limbs > distol

b) myotonic phenomenon :- * resp muscles > recruyent

* delayed relaxation after muscle contraction either voluntorly or mechanical.

* affect tongue muscles of hard – difficulty relaxing hrip

Jaw > difficult cheering

• with repeated contraction ( worm up phenomnor )

• extramuscular manifestations;

heart > conduction defect

eye > Gtaract

149
endocrinal > testicular atrophy , infertility frontal baldness

CNS > mental retordation.

Diagnosis : DNA aralysis

Management : Genetic counseling

Regular ECG :- in conduction block > pacemaker

Treatment of chest infection

Treatment of cataract

Myotonia Congenita

• AR

• Age : first and second decode

• Sex : female more

• CIP :

• Generalized myotonia decrease with exercise and warm and increase by rest
and cold

• Hypertrophy of the muscles

• Transient weakness of muscles

Diagnosis : EMG

DNA analysis

Treatment mexilitire

Paramyotonia congenital

Myotonia precipitated and increased by execcise and cold.

Periodic por-lysis

150
Primary hypolcalemic primary hyperlcalemic

* attacks fgeneralized weakness paring bulbor and resp.

* preapating factors :

Carbohydrates diet cold , fasting , rest , emotional stress

Emotioned upset

* treatment

- avoid precipitation factors

- oral potassium chloride - lowdase

- acetozolamide - thicizide

- acetozolamide - inhalation y B-stimulant

151
 Inflammatory myopathy

Def : Diseases characterized by presence of inflammatory infiltrate within muscle.

Classifications:

• Idiopathic : Dermatoryositiss pohmyasits , inclusion body myositis

• Infective * associated with collagen disease

Idiopathic inflammatory myopathy

CIP : of dermatomyosits and polymyositis

Age : 5-14 years in dermato

50-60 years in poymyoscls

Onset : subacute in dermatomyasils

Gradul in polymyases

Rash – in 90 % Y dermatomyosils affect face , extensor suface f faints

erythmatus , photosensite

Weakness – proximal in upper limb , lower limb

Neck muscles

Bulbar , muscles

* Painful , tender , swollen muscle in dermatonyostis

* extramuscular manifestation

e.g: Paynaud disease arthralgia

* malignancy in 20 y. of deimatomyositis

Diagnosis :

- laboratory : * Elevation of ESR , CRP

* CK

152
 * Cirulating antibodies

- EMG

- Mescle biobsy

Treatment :

1) prednisilone : 1mg/kg body weight

2) immunosuppressive drugs : azathioprire

3) intravenous immunoloblin

poor prognosibe factors : old age , time of instiation of treatment , extcamuscular

manifestation

Indusion body myoscls

• age -0 > so years old

• males

CIP : early , weakness F quadriceps, muscle finge flexors

Late : dygsphogio

Diagnosis > muscles biobsy

Treatment > immunospreastise drugs , ineffective

153
 Disorders Of The

Neurmoucular Ganction

[Link] Elkapany
Definition : > clinical condition : related to dysfunction at neuromuscular junction :

1- myasthenia Gravis

2- lambert eaten

3- congenital myasthenic syndrome

4- acquired neuromyotonia C Iscac`s syndrome

each is related 10 disturbedion channel function

Myasthenia Gaus

- Autoimmune disease with production of antibodies against acety \ choline

receplor of neuromuscular function leading to destruction

- CIP

- Age : 20-40 years ( females > 20-24 years )

( males > 30-34 years )

- Sex : female more

- Easy fatiguability espiceally on repetition of movement

- Weakness of :

• Ocular muscles >> ptosis, ophthalmoploie diplopia

Presenting symptom in 90 %

If no spread of weakness more then 2 years >> pure

oocular nyasthenia.

154
 • facial muscles cetractors of argle fmouth

• bulbar muscles >> dysphogia and dysorthn

• nesck muscles >> extensors

• limb muscles : roximal more in UL > LL

• respiratory muscles :

- weakness varies durig >> coorse of the day

activity

emotions

menestrvation

infection

- incidence of other autoimmune diseases

Diagnosis :

1- Clinical tests :

a) induction of fatigue >> maintain upward gaze >> pasis count from 1-50 >>
dysorthria

b) walker`s test

• sphygmomanometer is applied toarm and raise pressure above systolic

• the patient is asked to perform motor activity

• relase the sphygmomanometer - ptosis

c) phormacobgiccal tests

• prostigmine test : injection of 215 mg prostigmine + one ampoule atropine

>>> improvement of ptosis within 10-30 minutes in myaestheria

155
 • tensilon test : Edrophonivm infection intravenous in proveent F ptasis within 2
minutes

- Serological : -

 Anti-acety\ choline receptor antibody : +ve in 90% of generalized myastheir

and 50 % of ocular myasthenia

 Antinuclear Ab. And thyroid functions

- Radiobgy : X-ray – CT chest to bletect

- Electromyography: repititviere supramax imcl stimulation

Decremental response 710 %

* single fibre EMG

- Treatment :

There are various sterategies used for treatment of myasthenia Gavis :

a) acety\ cholinesterase inhibitors

b) immunosuppressive agents

c) plasma exchange

d) thymectomy

the regimen depend on : age of the patient ,

presence or absence of enlorged thymus

concurrent medical problems

1- Acety\ cholinesterase inhibitors

• phridostigmine : 30 – 60 mg every 5 hours

• neostigmine

2- Corticost eriods : indication :

156
 - Generalized myasthenia above 50 years

- Pure ocular myasthenia

- If acely\cholire receplor AB is ve

- If no response to ant : cholinest erese drugs

* prednisilone 1.5 mg/ kg

3- Immunosuppressive drugs – azathioprire , methotraxate

If contraindication 10 steroid.

4- Thymectomy : indications :

* presence of thymomy

* Generalized myasthenia < 50 years

* acety\ cholin receptor AB the lead to remission in 1/3 y cases

5- Intravenous immunoglobulin , pasma excharge :

- both equal in ellicacy

- indications : in myasthenic crisis

- prior to thmectomy

Myasthenic Crisis :

• Should be differentiated from cholinergic crises by tensilon test

• Ph should be in ICU

• Monitoring pulmonary functions

• Intubation and mechanical ventilation

• Plasma exchange or Iv . Iy.

• Plus steroioy

157
 Lambert Eaton

- Presynaptic disorder

- Ab against Ca channel >> reluse F Ach

- 50% associated with lung cancer

- Clinical picture

- Weakness of lower limb >> gait disturbance

- Mild ptosis

- Autonomic F eatures : impotence and dry mouth

Diagnosis :

Serological >> antibodies again ca channel

- EMG >> murked >> compound action potential repitive stimulation :

increamental response

- Treatment :> Acety\ cholinesterase inhibitors >> variable response

3/4 diaminopyridine >> delay >> repotarization

158