autonomic nervous system

3. Examination of Autonomic nervous system
1- clinical
observation
2- clinical
tests
3- pharmacological
tests
3- investigations
2- Testing
Radiological
Electrophysiology
Body
Fluids

5. 1- clinical observation :
1- cerebral :
 Frontal lobe disorders  cognitive and memory
impairment which may be associated with incontinence d.t un
inhibited neurogenic bladder .
2- cranial nerves :
 2nd and 3rd CN exam. Is important in localization of the
lesions that produce asymmetrical pupils or absent pupillary
responses to light.
 Ischaemic lesions  pupil sparing 3rd CN palsy
while compressive lesion  affect pupil before EOMs
d.t. peripheral locality of constrictor fibres in 3rd CN.

6. 3- Motor / reflex / cerebellar / gait :
 Distal symmetrical weakness + areflexia  GB$ , toxic ,
drug reaction to vincristine
 Proximal ms weakness + areflexia  botulism , Eaton
lambert MG
 Spastic paraparesis + neurogenic bladder with detrusor-
sphincter dyssynergia (e.g., as in multiple sclerosis).
 Areflexia in the lower extremities + loss of the anal and
bulbocavernosus reflexes + hypotonic bladder, bowel
hypomotility, and sphincter incontinence  cauda equina
lesion.
 Extrapyramidal, pyramidal, cerebellar, and autonomic
deficits in varying combinations are characteristic of multiple
system atrophy (i.e., the Shy-Drager syndrome)

7. 4- Sensory :
 Distal, symmetrical loss of sensation to pinprick and
temperature is typical of the small-fiber peripheral neuropathies
associated with diffuse autonomic failure (e.g., diabetes and
amyloidosis).
 Insensitivity to pain occurs in patients with some hereditary
sensory and autonomic neuropathies, including familial
dysautonomia (Riley-Day syndrome).
 Loss of the vibration and joint position sense occurs in
paraneoplastic sensory ganglioneuronopathies and Sjِ gren's
syndrome, both of which are commonly associated with autonomic
failure.
 Hypersthesia and allodynia in a limb, associated with
vasomotor and sudomotor changes, occur in patients with damage
to a peripheral nerve (causalgia) or the poorly understood reflex
sympathetic dystrophy.

8. 2- clinical tests :
C.V.S
Pupil Lacrimal G.
Skin
GIT GUT

9. CVS
Assess cardio-
vagal
innervation
Assess cardio-
sympathatic
innervation
Heart rate response to
Deep
breathing
Valsalva
maneuver
Postural change
(30:15 ratio)
Blood pressure response to
Sustained
handgrip
Cold water
immersion
Mental
stress
Plasma catecholamine levels
and infusion tests
Orthostatic test
Head-up tilt table testing

10. 1- heart rate response to deep breathing :
 Heart rate increases during inspiration and decreases
during expiration.
 The variation of heart rate with respiration is known as
sinus arrhythmia and is generated by autonomic reflexes.
 The variation is primarily mediated by the vagus
innervation of the heart
 The heart rate response to deep breathing is maximal at
approximately six deep breaths per minute.
 The subject's age and the rate and depth of respiration
influence heart rate variation in response to deep breathing.
 It is the best noninvasive test for the assessment of cardiac
vagal innervation .

12.  Technique :-
- The Valsalva maneuver is typically performed by blowing through a
mouthpiece connected to a mercury manometer for 15 or 20 seconds.
- The mercury column of the manometer is maintained at 40mm.
 Phases :-
 The normal cardiovascular response to a Valsalva maneuver has four
phases :
 Phase 1  consists of a transient rise in arterial pressure and an
associated decrease in heart rate.
 Phase 2  the expiratory phase of the maneuver, there is a gradual
decrease in blood pressure followed by a recovery. An increase in heart
rate accompanies this phase.
 Phase 3  consists of a sudden brief decrease in blood pressure with an
accompanying increase in heart rate that occurs with the cessation of
straining.
 Phase 4  there is an increase in blood pressure above the resting value
(the “overshoot”) that is accompanied by a bradycardia.
2- heart rate response to valsalva maneuver :

13.  Phases 1 and 3 most likely reflect mechanical factors, whereas phases 2
and 4 are a consequence of sympathetic, vagal, and baroreflex interactions.
 The Valsalva ratio (i.e., the ratio between the tachycardia occurring
during the maneuver and the postmaneuver bradycardia) provides an index
of cardiac vagal function.
Maximum R-R interval after the strain (in phase IV)
Valsalva ratio = ----------------------------------------------------------------
Shortest R-R interval during the strain (in phase II)
Shortest R-R interval during the valsalva maneuver
Tachycardia Ratio = --------------------------------------------------------
Longest R-R interval before the valsalva maneuver

16.  Heart rate increases sharply on standing, peaking at
approximately 12 seconds (approximately the 15th beat).
 It then becomes progressively slower until approximately 20
seconds after standing (so that the 13th R-R interval is usually
the longest), and then it gradually rises again.
 This transient relative bradycardia is due to reflex activation
of efferent cardiac vagal fibers.
 These changes are reflected by the 30:15 ratio, which is
calculated by dividing the longest R-R interval around the
13th beat by the shortest R-R interval around the 15th beat
(RRmax 30/RRmin 15 ratio).
 In subjects with abnormal cardiovagal function, the
bradycardia is reduced or absent.
3- heart rate response to Postural Change
(the “30:15 Ratio”) :

18. 4- blood pressure response to sustained handgrip :
 The mechanism : Persistent muscle contraction causes blood
pressure and heart rate to increase d.t the exercise reflex, which
withdraws parasympathetic activity and increases sympathetic
activity.
 This test : requires the patient to apply and maintain grip at
30% maximal activity for up to 5 minutes
 the diastolic blood pressure should rise more than 15 mm Hg.

19. 5- blood pressure response to mental stress :
 Mental stresses such as arithmetic, emotional pressure,
and even sudden noise leads to increase in blood pressure
and heart rate d.t. increased sympathatic outflow.
 This test has been used as a measure of sympathetic
efferent function that has the advantage of not requiring
direct afferent stimulation

20. 6- blood pressure response to cold water immersion
( cold pressor test ) :
 In 1932, Hines and Brown noted an increase in blood
pressure after submerging a patient's hand in ice water.
 The afferent limb of the reflex is somatic, and the efferent
limb is sympathetic.
 It`s difficult and not sensitive .

21.  Beat-to-beat recordings of the blood pressure during a
Valsalva maneuver may be used to measure cardiac
adrenergic function.
 Sympathetic failure is characterized by :
1- profound decrease of blood pressure in phase 2 .
2- Absence of the blood pressure overshoot in phase 4 of
the Valsalva maneuver.
7- blood pressure response to valsalva maneuver :

22. 8- cardiovascular response to postural change :
 Measurement of changes in blood pressure and heart rate
induced by passive tilt or active standing is the most useful test
of sympathetic function.
1- Head-up tilt table testing :
 During upright tilt to 60 degrees or more,
 Normal subjects undergo a transient reduction in systolic,
diastolic, and mean blood pressure, followed by a recovery
within 1 minute. The heart rate also increases by 10 to 20 beats
per minute.
 Patients with adrenergic failure have a marked reduction in
systolic, diastolic, and pulse pressure with no recovery, and
they have an inadequate compensatory tachycardia.

25. 2- Orthostatic Test :
 Technique : blood pressure and heart rate are measured while the
patient is supine and after he or she has been standing for at least 3
minutes.
 Normally : SBP  ↓ 5 – 20 mmHg
DPB  no change or only a slight rise
HR   5 – 20 B/M
 Reproducible fall of more than 20mmHg in systolic pressure or of more
than 10mmHg in diastolic pressure within 3 minutes of adopting the erect
position  Orthostatic hypotension
 N.B :
- In patients with severe orthostatic intolerance, it is useful to monitor the length of
time the patient can stand in place before he or she experiences symptoms. Severe
orthostatic hypotension results in a “standing time” of less than 30 seconds
- The presence of orthostatic hypotention without reflex tachycardia indicate
sympathatic and cardiovagal failure . If reflex tachycardia is present ,
hypovolemia should be excluded.

26. 3- plama catecholamine levals & infusion tests :
 In normal subjects, plasma NE levels double with the
assumption of the upright posture in view of initiation of
vasopressor responses, which are sympathetic and adrenergic.
 In preganglionic sympathetic disorders such as multisystem
atrophy  resting supine norepinephrine levels are normal
but fail to rise when at standing because of the lack the
preganglionic drive.
 In postganglionic sympathetic disorders, such as progressive
autonomic failure  resting supine norepinephrine levels are
low and fail to rise when at standing.

27.  Infusion tests :
1- Edrophonium infusion test :
( Edrophonium, a cholinomimetic agent, induces the release of NE
by stimulating the sympathetic ganglia. )
2- Tyramine infusion test :
( Tyramine, an indirect sympathomimetic agent, which releases
NE from sympathetic terminals. )
3- NE & other α-adrenergic agonists infusion test :
( assess denervation supersensitivity and baroreflex function. )

28. pupil
Clinically :
 Ocular sympathatic  dilator pupillae ms.(most active in dim light).
 Ocular parasympathatic  constrictor pupillae(most active in bright light).
 so, in parasympathatic lesion  anisocoria is greater in bright light
(large pupil abnormal)
& in sympathatic lesion  anisocoria is graeter in dim light
(small pupil abnormal)
 so, assess pupillary size in dim and bright light.
Confirm lesion Localize lesion
Cocaine test Hydroxyamphetamine test
pharmacological

30. 1- confirm diagnosis :
1- cocaine 5-10% test :
 prevent NE reuptake at sympath. N. synapses and causes
pupillary dilation in eyes with intact sympathetic innervation.
 Cocaine has no effect in eyes with impaired sympathetic
innervation, regardless of the lesion location.
 Technique :- 2 cocaine drops in every eye  anisocoria ≥
1mm is considered a positive result.
 If the diagnosis of Horner's syndrome is clear clinically, then
use of cocaine or apraclonidine drops to confirm the diagnosis
can be avoided, as their administration will interfere with the
hydroxyamphetamine test for localization.

31. 2- apraclonidine 0.5% test :
 (α- adrenergic agonist )
 Weak α1(mediate pupilary dilatation) and strong α2
( downregulate NE ralease at NMJ)
 In a Horner's pupil, denervation supersensitivity to the alpha-1
receptor will cause that pupil to dilate (usually by about 2 mm),
while alpha-2 stimulation in the normal eye will cause that
pupil to constrict slightly (usually by <1 mm).
Reverse anisocoria
 Technique :- one to two drops of 0.5 percent apraclonidine
instilled in both eyes causes a reversal of anisocoria in patients
with Horner's syndrome.
 Comparison testing in small series of patients suggests that this
test compares favorably with cocaine in the diagnosis of
Horner's syndrome.

32. 2- for localization :
1- hydroxyamphetamine test :
 release stored NE from postganglionic adrenergic n. endings .
 differentiate 1st &2nd order lesions ( perganglionic ) from 3rd
order lesions ( postganglionic ) .
 There is no pharmacologic test to distinguish between first
from second-order lesions.
 Because cocaine may interfere with the uptake and efficacy of
hydroxyamphetamine drops, it is recommended that 24 to 72
hours elapse between the two tests .
 Technique :- One hour after instillation of 1 percent
hydroxyamphetamine, a normal pupil and a first or second-
order Horner's pupil will dilate, whereas a third-order
Horner's pupil will not dilate as well as the normal pupil .
 Sensitivity of 93 to 96 % and Specificity of 84 % for detecting
postganglionic lesions .
 This test is not reliable in children in whom transynaptic
degeneration occurs .

33. 2- pholedrine test :
- It is hydroxyamphetamine derivative .
- It may be more available than hydroxyamphetamine in
some locations.
- The test using 1 percent pholedrine is performed in the
same manner as with hydroxyamphetamine .

35. Lacrimal G.
Schirmer's test
 Assess parasympathatic innervation
to lacrimal G.
 Normally; the length of wettness of the strip
is 15 mm after 5 min.
 in parasympathatic lesion;
reduced or absent tearing

38. GIT
 Sympathetic denervation may be identified
by various neurochemical studies, including
the norepinephrine response to edrophonium.
 Parasympathetic denervation may be identified
by the plasma pancreatic polypeptide response
to sham feeding or hypoglycemia

39. GUT
 The bulbocavernosus and anal reflexes
are somatic reflexes integrated at the S2–S4 levels,
 The scrotal and internal anal reflexes
are autonomic reflexes integrate at the S2–S4 and
T12–L2 levels, respectively.

40. Skin & sweat G.
Quantitative sudomotor
axon reflex test
Thermoregulatory
sweat test
Sympathetic skin
response test
Histamine
flare
Pilocarpine
test

41. 1- Quantitative sudomotor axon reflex test (QSART) :
 is the most sensitive test of distal small fiber neuropathy
(see the images below).
Technique :-
 This test involves iontophoresis of acetylcholine (ACh) onto
the skin to stimulate sympathetic C-fibers in the sweat
glands.
 The sweat response that is evoked is quantitated using a
sudomotor, which measures the humidity of the evoked
sweating response.
 Generalized dysautonomias, complex regional pain
syndrome, atopic dermatitis, anticholinergic medication use,
and abnormalities of the skin and sweat glands can interfere
with the test results.

44. 2- Thermoregulatory sweat test :
 In the thermoregulatory sweat test (TST), patients are
placed in a warming cabinet to provoke sweating.
 Their sweating pattern is then assessed by the color change
of alizarin powder dusted over the body, limbs, and forehead
(see the following image)

46. 3- Sympathetic skin response test :
 It is based on the fact that electrodermal activity reflects
sympathetic cholinergic sudomotor function, which induces
changes in resistance of skin to electric conduction.
 Many modalities of stimulation suffice to elicit the potential
reflexly, including electrical depolarization, startling auditory
sound or deep inspiratory gasps.
 The potentials in the hands have larger amplitudes and shorter
latencies than those in the feet. The latency is about 1.5 seconds in
the hand and about 2 seconds in the foot following an eliciting
stimulation.
 The major contributor to latency is the efferent conduction
along the sudomotor pathways, which are small, unmyelinated C
fibers.

47. 4- Sweat Imprint :
 A sweat imprint is formed by the secretion of active sweat
glands into a plastic or silicone mold in response to
iontophoresis of a cholinergic agonist.
 This test can be used to determine :-
- sweat gland density
- sweat droplet size
- sweat volume per unit of area.

48. 5- Pilocarpine test :
 A bedside intradermal injection of pilocarpine can be used to
assess the sweat glands;
 a supersensitive response to diluted pilocarpine indicates the
presence of postganglionic sympathetic sudomotor denervation.
6- Histamine flare :
 Intradermal injection of histamine produces a “triple
response” (erythema, flare, and wheal) through an axon reflex
mediated by nociceptive C-afferent fibers.
 Loss of the histamine flare indicates severe loss or absence of
nociceptive C axons, as in patients with familial dysautonomia
or peripheral neuropathies affecting the sympathetic nerves

50. 3- Investigations :
1- Neuroimaging :
Magnetic resonance imaging (MRI) is useful for the evaluation of
patients with focal or organ-specific autonomic syndromes .
 MRI Brain : indicated for the detection of hypothalamic lesions,
lateral medullary infarctions, syringomyelia, or lesions in the
cavernous sinus that produce Horner's syndrome . it may show
atrophy of the basal ganglia, pons, or cerebellum in patients with
multiple system atrophy .
 MRI Neck : is required when a diagnosis of paragangliomas arising
from the carotid body or the vagus nerve is considered in patients with
severe baroreflex failure.
 MRI abdomen : can localize pheochromocytomas arising from
chromaffin cells in the adrenal medulla or elsewhere in the abdomen,
and imaging of the neck, chest, and pelvis should be used when
pheochromocytomas are considered.

51. 2- Neurophysiology:
1- Electromyography (EMG) and nerve conduction velocities
(NCVs) :
 Evaluation of patients with peripheral neuropathy. However, the studies may
be normal in conditions that selectively affect small nerve fibers.
 Small-fiber function may be assessed using quantitative sensory testing to
determine the sensory threshold for heat and cold sensation; these sensory
modalities are mediated by the C- and A-delta nerve fibers. This technique
measures the intensity of a stimulus necessary to evoke a specific sensation.
 Evaluation of peripheral nerve injuries that may result in focal autonomic
abnormalities.
 Identify the cause of the predominantly cholinergic autonomic abnormalities
that accompany the prejunctional disorders of neuromuscular transmission (e.g.,
botulism, the Lambert-Eaton myasthenic syndrome, and the autonomic
abnormalities that accompany paraneoplastic sensory ganglioneuronopathy).
 EMG of the external anal sphincter may show denervation in patients with
lesions of the conus or cauda equina and in patients with multiple system atrophy.

52. 2- Electrodermal activity :
the sympathetic skin response or peripheral autonomic surface potential.
 Origin : generated by the sweat glands and overlying epidermis .
 Center : mediated by supraspinal sites that include the orbitofrontal
cortex, the posterior hypothalamus, the dorsal thalamus, and the
ventrolateral reticular formation.
 Stimulus : occurs spontaneously and can be evoked by stimuli such
as respiration, startling, mental stress, and electrical stimuli,
 Uses : to assess sudomotor function.
Test :It consists of a slow change in the electrical potential of the skin
of the palms and feet that depends on sweat production and is evoked
reflexively by unexpected noise, deep inspiration, and electrical stimuli.
Absence of the sympathetic skin response occurs in patients with
autonomic failure,
 It has limited specificity and no localizing value.

53. 3- Microneurographic recordings of activity in sympathetic
fibers innervating muscle and skin :
 Allow direct assessment of sympathetic vasoconstrictor and
skin sudomotor outflows, respectively.
 However, because this technique is laborious, invasive, and
requires considerable expertise as well as a very cooperative
patient, it remains only a research tool.

54. 3- Electroencephalography :
 may show epileptiform activity in the temporolimbic
areas, which may be associated with syncope or other
paroxysmal autonomic phenomena.
4- Sleep polysomnograms :
 in patients with multiple system atrophy may allow the
physician to make a diagnosis of sleep apnea or rapid eye
movement sleep behavior disorder.

55. 3- Body fluids and tissue analysis:
1- Blood tests useful in the evaluation of patients with autonomic failure include :
1- blood glucose and glycosylated hemoglobin (diabetes)
2- protein immunoelectrophoresis and genetic tests for the transthyretin variant
(amyloidosis),
3- vitamin B12 (pernicious anemia),
4- erythrocyte sedimentation rate,
5- anti-nuclear antibody (connective tissue diseases(,
6- extractable nuclear antigen )Sjِ gren's disease(,
7- anti-neuronal nuclear )anti-Hu (antibody
8- Purkinje cell cytoplasmic antibodies type 2 (PCA-2),
9- antibodies to the neuron cytoplasmic protein,
10- Collapsin response-mediator protein-5 (CRMP-5) (paraneoplastic autonomic
neuropathy),
11- human immunodeficiency virus serology, and, in select cases, porphyrins
(acute intermittent porphyria) or α-galactosidase (Fabry's disease).
12- Measurements of plasma cortisol in the morning and evening and, as
previously mentioned, plasm catecholamines in the supine and standing positions
may be helpful in the evaluation of patients with orthostatic hypotension.

56. N.B. : Some patients with acute or subacute autonomic neuropathy have
antibodies against the α3 subunit of the ganglionic nicotinic acetylcholine
receptor, and autonomic dysfunction develops in rabbits that are immunized
against the ganglionic acetylcholine receptor, suggesting that the antibodies
are the cause of the disorder
(autoimmune autonomic neuropathy).
2- Cerebrospinal fluid examination
 may show albuminocytological dissociation with an elevated protein
concentration and no pleocytosis in patients with Guillain-Barré syndrome
and other acute pandysautonomias.
3- Biobsy :
 Abdominal fat aspirate, rectal biopsy, or sural nerve biopsy should be
considered in patients in whom amyloid neuropathy or Fabry's disease is
suspected
 salivary or lacrimal gland biopsy should be done in patients in whom
Sjogren's syndrome is suspected .