didatic letures for undergraduate of MEDICAL

1. CNS- Disorders of ANS

2. Schematic representation of the
autonomic nervous system.

18. Classification of Clinical Autonomic Disorder

19. I. Autonomic Disorders with Brain
Involvement
• A. Associated with multisystem degeneration
1. Multisystem degeneration: autonomic failure clinically prominent
a. Multiple system atrophy (MSA)
b. Parkinson’s disease with autonomic failure (PD with AF)
c. Diffuse Lewy body disease with autonomic failure(DLB Disease with AF)
2. Multisystem degeneration: autonomic failure clinically not usually
prominent
a. Parkinson’s disease without autonomic failure
b. Other extrapyramidal disorders (inherited spinocerebellar atrophies, progressive
supranuclear palsy, corticobasal degeneration, Machado-Joseph disease, fragile X
syndrome [FXTAS])

20. I. Autonomic Disorders with Brain
Involvement
• B. Unassociated with multisystem degeneration (focal CNS
disorders)
• 1. Disorders mainly due to cerebral cortex involvement
a. Frontal cortex lesions causing urinary/bowel incontinence
b. Focal seizures (temporal lobe or anterior cingulate)
c. Cerebral infarction of the insula
• 2. Disorders of the limbic and paralimbic circuits
a. Shapiro’s syndrome (agenesis of corpus callosum, hyperhidrosis, hypothermia)
 b. Autonomic seizures
c. Limbic encephalitis

21. I. Autonomic Disorders with Brain Involvement
• B. Unassociated with multisystem degeneration (focal CNS
disorders)
3. Disorders of the hypothalamus
4. Disorders of the brainstem and cerebellum

22. I. Autonomic Disorders with Brain:Hypothalamus
Involvement
• B. Unassociated with multisystem degeneration (focal CNS disorders)
3. Disorders of the hypothalamus
• a. Thiamine deficiency (Wernicke-
Korsakoff syndrome)
• g. Disturbances of temperature regulation
(hyperthermia, hypothermia)
• b. Diencephalic syndrome • h. Disturbances of sexual function
• c. Neuroleptic malignant syndrome • i. Disturbances of appetite
• d. Serotonin syndrome • j. Disturbances of BP/HR and gastric function
• e. Fatal familial insomnia • k. Horner’s syndrome
• f. Antidiuretic hormone (ADH)
syndromes (diabetes insipidus, inappropriate ADH
secretion)

23. I. Autonomic Disorders with Brain:Brain stem &C.
cere Involvement
• B. Unassociated with multisystem degeneration (focal CNS disorders)
3. Disorders of the hypothalamus
• a. Posterior fossa tumors • f. Baroreflex failure
• b. Syringobulbia and Arnold-Chiari
malformation
• g. Horner’s syndrome
• c. Disorders of BP control (hypertension,
hypotension)
• h. Vertebrobasilar and lateral medullary
(Wallenberg’s) syndromes
• d. Cardiac arrhythmias • i. Brainstem encephalitis
• e. Central sleep apnea

24. II. Autonomic Disorders with Spinal Cord
Involvement
• A. Traumatic quadriplegia
• B. Syringomyelia
• C. Subacute combined
degeneration
• D. Multiple sclerosis and
neuromyelitis optica
• E. Amyotrophic lateral sclerosis
• F. Tetanus
• G. Stiff-person syndrome
• H. Spinal cord tumors

25. III. Autonomic Neuropathies-Acute
A. Acute/sub acute autonomic neuropathies
 a. Subacute autoimmune autonomic
ganglionopathy (AAG)
 b. Subacute paraneoplastic autonomic
neuropathy
 c. Guillain-Barré syndrome
 d. Botulism
 e. Porphyria
 f. Drug induced autonomic neuropathies-
stimulants, drug withdrawal, vasoconstrictor,
vasodilators, beta-receptor antagonists, beta-
agonists
 g. Toxin-induced autonomic neuropathies
 h. Subacute cholinergic neuropathy

26. III. Autonomic Neuropathies- Chronic
B. Chronic peripheral autonomic neuropathies
1. Distal small fiber neuropathy
2. Combined sympathetic and
parasympathetic failure
a. Amyloid
b. Diabetic autonomic neuropathy
c. AAG (paraneoplastic and idiopathic)
d. Sensory neuronopathy with
autonomic failure
2. Combined sympathetic and parasympathetic
failure
 e. Familial dysautonomia (Riley-Day syndrome)
 f. Diabetic, uremic, or nutritional deficiency
 g. Geriatric dysautonomia (age >80 years)
3. Disorders of orthostatic intolerance: reflex
syncope; POTS; prolonged
bed rest; space flight; chronic fatigue

27. Common types of Autonomic
Disorders
• Orthostatic Hypotension. ...
• Postprandial Hypotension. ...
• Multiple System Atrophy. ...
• Pure Autonomic Failure. ...
• Afferent Baroreflex Failure. ...
• Familial Dysautonomia.

28. Pathology of Disorders of the ANS
• Disorders of the ANS may result from pathology of either the CNS or
the peripheral nervous system (PNS)
Signs and symptoms may result from interruption of the
afferent limb,
CNS processing centers, or
efferent limb of reflex arcs controlling autonomic responses.

29. Orthostatic hypotension (OH).

60. Autonomic Testing
• Deep Breathing Test
• Valsalva Maneuver
• Tilt Table Testing For Syncope
• Quantitative Sudomotor Axon Reflex Test (QSART).
•
• Thermoregulatory Sweat Test (TST)

61. Horner’s Syndrome

72. NMS Vs SS

77. Thank you

80. Non neurogenic Causes of Orthostatic Hypotension
Cardiac Pump Failure
Myocardial infarction
Myocarditis
Constrictive pericarditis
Aortic stenosis
Tachyarrhythmias
Bradyarrhythmias
Salt-losing nephropathy
Adrenal insufficiency
Diabetes insipidus
Venous obstruction

81. Non neurogenic Causes of Orthostatic Hypotension
Reduced Intravascular Volume Metabolic
Straining or heavy lifting, urination,
defecation
Dehydration
Diarrhea, emesis
Hemorrhage
Burns
Adrenocortical insufficiency
Hypoaldosteronism
Pheochromocytoma
Severe potassium depletion

82. Non neurogenic Causes of Orthostatic Hypotension
Venous Pooling Medications
• Alcohol
• Postprandial dilation of splanchnic vessel beds
• Vigorous exercise with dilation of skeletal vessel
beds
• Heat: hot environment, hot showers and baths,
fever
• Prolonged recumbency or standing
• Sepsis
• Antihypertensives
• Diuretics
• Vasodilators: nitrates, hydralazine
• Alpha- and beta-blocking agents
• Central nervous system sedatives:
barbiturates, opiates
• Tricyclic antidepressants
• Phenothiazines

83. The site of reflex interruption
• The site of reflex interruption is usually established by the clinical
context in which the dysautonomia arises, combined with judicious
use of ANS testing and neuroimaging studies.
The presence or absence of CNS signs,
association with sensory or motor polyneuropathy,
medical illnesses,
medication use,
and family history are often important considerations.

84. • It is important to recognize the modulating effects of age and
duration of disease.
• For example, OH typically produces lightheadedness when of acute
onset, but may present with subtle cognitive manifestations in
chronic disease.
• Specific symptoms of orthostatic intolerance are diverse.

85. Symptoms of Autonomic Dysfunction
• Clinical manifestations can result from loss of function, overactivity, or
dysregulation of autonomic circuits.
• Disorders of autonomic function should be considered in patients with
 unexplained OH,
syncope,
sleep dysfunction,
altered sweating (hyperhidrosis or hypohidrosis),
impotence,
constipation or other GI symptoms (bloating, nausea, vomiting of old food,
diarrhea),
 or bladder disorders (urinary frequency, hesitancy, or incontinence).

86. • Symptoms may be widespread or regional in distribution.
• An autonomic history focuses on systemic functions (orthostatic
symptoms, BP, heart rate, sleep, fever, sweating)
• and involvement of individual organ systems (pupils, bowel, bladder,
sexual function).

87. • Autonomic symptoms may vary dramatically, reflecting the dynamic
nature of autonomic control over homeostatic function.
For example, OH might be manifest
only in the early morning,
following a meal,
with exercise,
or with raised ambient temperature, depending on the regional
vascular bed affected by the dysautonomia.

88. APPROACH TO THE PATIENT
Orthostatic Hypotension and Other ANS Disorders

89. The first step in the evaluation of symptomatic OH is the exclusion of
treatable causes.
• The history should include a review of medications that may affect the
ANS.
• The main classes of drugs that may cause OH are
diuretics,
antihypertensive agents (preload reducers, vasodilators, negative inotropic
or chronotropic agents),
antidepressants (tricyclic antidepressants and SSRIs),
ethanol, opioids, insulin, dopamine agonists, and barbiturates.

91. History recording
• However, the precipitation of OH by medications may also be the first
sign of an underlying autonomic disorder.
• The history may reveal an underlying cause for symptoms
• e.g., diabetes, Parkinson’s disease
• or specific underlying mechanisms (e.g., cardiac pump failure,
reduced intravascular volume).

92. • The relationship of symptoms
to meals (splanchnic pooling),
standing on awakening in the morning (intravascular volume depletion),
ambient warming (vasodilatation),
or exercise (muscle arteriolar vasodilatation) should be sought.

93. Recording supine and standing pulse and BP
• Standing time to first symptom and to presyncope should be followed for
management.
• Physical examination includes measurement of supine and standing pulse and BP.
• OH is defined as a sustained drop in systolic (≥20 mmHg) or diastolic (≥10 mmHg)
BP after 3 min of standing.
• In non-neurogenic causes of OH (such as hypovolemia), the BP drop is
accompanied by a compensatory increase in heart rate of >15 beats/min.

94. Neurologic examination
• Neurologic examination should include
mental status (neurodegenerative disorders such as Lewy body
dementia can be accompanied by significant dysautonomia),
 cranial nerves (abnormal pupils with Horner’s or Adie’s syndrome),
 motor tone (parkinsonian syndromes),
motor strength and sensation (polyneuropathies).

95. • In patients without a clear diagnosis initially, follow-up evaluations
every few months or whenever symptoms worsen may reveal the
underlying cause

96. Disorders of autonomic function should be considered in
patients
with symptoms of
altered sweating (hyperhidrosis or hypohidrosis),
 gastroparesis (bloating, nausea, vomiting of old food),
impotence,
constipation,
or bladder disturbances (urinary frequency, hesitancy, or
incontinence).

97. Autonomic Testing

99. Deep Breathing Test and Valsalva Maneuver
• These tests measure your heart rate and blood pressure while
doing certain types of breathing.
• For both tests, a provider will place electrodes on your chest
and a small blood pressure cuff on your finger.
For a deep breathing test, you will take slow, deep breaths for
one minute.
For the Valsalva maneuver, you will breathe out forcefully
through a mouthpiece while your nose is pinched shut.
• The electrodes and cuff will record your heart rate and blood
pressure.

100. Heart Rate Variation With Deep Breathing
• This tests the parasympathetic component of cardiovascular reflexes
via the vagus nerve.
• Results are influenced by multiple factors including the subject’s
position (recumbent, sitting, or standing), rate and depth of
respiration (6 breaths per minute and a forced vital capacity [FVC]
>1.5 L are optimal), age, medications, weight, and degree of
hypocapnia.
• Interpretation of results requires comparison of test data with results
from age-matched controls collected under identical test conditions.

101. HRDB
For example,
• the lower limit of normal heart rate variation with deep breathing in
persons 15–20 beats/ min,
• but for persons aged >60 it is 5–8 beats/min.
• Heart rate variation with deep breathing (respiratory sinus
arrhythmia) is abolished by the muscarinic ACh receptor antagonist
atropine
• but is unaffected by sympathetic postganglionic blockade (e.g.,
propranolol).

102. Valsalva Response
• This response assesses the integrity of the baroreflex control of heart
rate (parasympathetic) and BP (sympathetic adrenergic).
• Under normal conditions, increases in BP at the carotid bulb trigger a
reduction in heart rate (increased vagal tone), and decreases in BP
trigger an increase in heart rate (reduced vagal tone).

104. • The Valsalva response is tested in the supine position.
• The subject exhales against a closed glottis (or into a manometer
maintaining a constant expiratory pressure of 40 mmHg) for 15 s while
measuring changes in heart rate and beat-to-beat BP.
• Without directly measuring expiratory pressure, heart rate and beat-to
beat blood pressure the Valsalva maneuver cannot be interpreted correctly

105. Tilt Table Test.
This test measures blood pressure and heart rate as change of posture and
position.
During the test:
pt will lie flat on a motorized table that has a footrest.
Soft safety straps will be placed across pt’s body.
A health care provider will put electrodes on chest and blood pressure
cuffs on one of pt’s arms and a finger.
An IV line may also be placed in pt’s arm or hand to inject medicine or
fluids if needed.

106. • Pt will remain flat on the table for about 15 minutes.
• A health care provider will tilt the table to an almost standing position for
up to 45 minutes.
• care provider will check pt’s blood pressure and heart rate.
• If the test causes you to faint, the table will be quickly returned to the flat
position.

107. Tilt test
• Orthostatic BP Recordings Beat-to-beat BP measurements
determined in supine, 70° tilt, and tilt-back positions are useful to
quantitate orthostatic failure of BP control.
• Allow a 20-min period of rest in the supine position before assessing
changes in BP during tilting.
• The BP change combined with heart rate monitoring is useful for the
evaluation of patients with suspected OH or unexplained syncope

108. Tilt Table Testing For Syncope
• The great majority of patients with syncope do not have autonomic
failure.
• Tilt table testing can be used to make the diagnosis of vasovagal
syncope with sensitivity, specificity, and reproducibility.
• A standardized protocol is used that specifies the tilt apparatus, tilt
angle, and duration of tilt.

109. Quantitative Sudomotor Axon Reflex Test
(QSART).
• This test measures the function of the nerves that control sweating. During
the test:
• care provider will place electrodes on pt’s foot, arm, and leg.
• The electrodes will contain a substance that stimulates sweating.
• A mild electrical current will be sent through the electrodes. Pt might feel a
warm, tingling sensation as this is done.
• A computer will analyze how pt’s nerves and sweat glands react to the
electrical current.
• The test takes about 45 minutes to an hour to complete.

110. Quantitative Sudomotor Axon Reflex Test (QSART)
• Sudomotor Function Sweating is induced by release of ACh from sympathetic
postganglionic fibers.
• The quantitative sudomotor axon reflex test (QSART) is a measure of regional
autonomic function mediated by ACh-induced sweating.
• A reduced or absent response indicates a lesion of the postganglionic sudomotor
axon. For example, sweating may be reduced in the feet as a result of distal
polyneuropathy (e.g., diabetes).

111. Thermoregulatory Sweat Test (TST).
• This test measures how well your body sweats in a warm environment.
During the test:
• A special powder will be applied to pt’s skin.
• Pt will lie in a special room that will be slowly heated up to stimulate
sweating. The heat and humidity may be a little uncomfortable.
• The powder will change color as pt sweat.
• The pattern of pt’s sweat can show if pt sweating normally.
• The test takes usually takes 40-65 minutes to complete.

112. Thermoregulatory Sweat Test (TST)
• The thermoregulatory sweat test (TST) is a qualitative measure of global sweat
production in response to an elevation of body temperature under controlled
conditions.
• An indicator powder placed on the anterior surface of the body changes color
with sweat production during temperature elevation.
• The pattern of color change measures the integrity of both the preganglionic and
postganglionic sudomotor function.

113. • A postganglionic lesion is present if both QSART and TST show absence of
sweating.
• In a preganglionic lesion, the QSART is normal but TST shows
anhidrosis

114. Bladder Ultrasound.
• This test is used to check for problems with pt’s bladder, which is
controlled by autonomic nerves.
• The ultrasound is done after pt urinate to see how much urine is left in the
bladder.
• USG pre voiding & post voiding to measure residual urine

116. Neuroleptic Malignant Syndrome

130. TREATMENT
Autonomic Failure

131. Nonpharmacologic approaches are summarized in
this table

132. Thank you

133. Management of autonomic failure
• Management of autonomic failure is aimed at specific treatment of the cause and
alleviation of symptoms.
• Of particular importance is the removal of drugs or amelioration of underlying
conditions that cause or aggravate the autonomic symptoms, especially in the
elderly.
• For example, OH can be caused or aggravated by
antihypertensive agents,
antidepressants,
levodopa or dopaminergic agonists,
ethanol,
opioids, and barbiturates
insulin,

134. Patient Education
Only a minority of patients with OH require drug treatment.
All patients should be taught the mechanisms of postural normotension
 and the nature of orthostatic stressors (time of day and the influence of meals,
heat, standing, and exercise).
Patients should learn to recognize orthostatic symptoms early (especially subtle
cognitive symptoms, weakness, and fatigue) and to modify or avoid activities that
provoke episodes.

135. BP log and dietary education
Other helpful measures may include keeping a BP log and dietary education
(salt/fluids).
Learning physical counter-maneuvers that reduce standing OH
and practicing postural and resistance training
and cardiovascular reconditioning are helpful measures.

136. Symptomatic Treatment
• Nonpharmacologic approaches are summarized
• Adequate intake of salt and fluids to produce a voiding volume between 1.5 and
2.5 L of urine (containing >170 meq/L of Na+) each 24 h is essential.
• Sleeping with the head of the bed elevated will minimize the effects of supine
nocturnal hypertension.

137. • Prolonged recumbency should be avoided when possible.
•
• Patients are advised to sit with legs dangling over the edge of the bed for
several minutes before attempting to stand in the morning;
• other postural stressors should be similarly approached in a gradual
manner.

138. • One maneuver that can reduce OH is leg-crossing with maintained contraction of
leg muscles for 30 s; this compresses leg veins and increases systemic resistance.
• Compressive garments, such as compression stockings or abdominal binders, are
helpful on occasion but are uncomfortable for many patients.
• For transient worsening of OH, drinking two 250-mL (8-oz) glasses of water within
5 min can raise standing BP 20–30 mmHg for about 2 h, beginning ~5 min after
the fluid load.

139. • The patient can increase intake of salt and fluids (bouillon treatment),
• increase use of physical counter-maneuvers (elevate the legs when
supine),
• or temporarily resort to a full-body stocking (compression pressure 30–40
mmHg).

140. Midodrine
If these measures are not sufficient, additional pharmacologic treatment may be
necessary.
• Midodrine, a directly acting α1 -agonist that does not cross the blood-brain
barrier, is effective. It has a duration of action of 2–4 h.
• The usual dose is 5–10 mg orally tid, but some patients respond best to a
decremental dose (e.g., 15 mg on awakening, 10 mg at noon, and 5 mg in the
afternoon).
• Midodrine should not be taken after 6:00 p.m.
• Side effects include pruritus, uncomfortable piloerection, and supine
hypertension, especially at higher doses.

141. Other drugs & Fludrocortisone
• Droxidopa (Northera) for treatment of neurogenic OH associated with PAF, PD, or
MSA is effective in decreasing symptoms of OH.
• Pyridostigmine appears to improve OH without aggravating supine hypertension
by enhancing ganglionic transmission (maximal when orthostatic, minimal when
supine), but with only modest clinical effects on BP
• Fludrocortisone will reduce OH but aggravates supine hypertension. At doses
between 0.1 mg/d and 0.3 mg bid orally, it enhances renal sodium conservation
and increases the sensitivity of arterioles to NE.

142. Postprandial OH may respond to several measures.
Frequent, small, low-carbohydrate meals may diminish splanchnic
shunting of blood after meals and reduce postprandial OH.
 Prostaglandin inhibitors (ibuprofen or indomethacin) taken with
meals
or midodrine (10 mg with the meal) can be helpful.
The somatostatin analogue octreotide can be useful in the treatment
of postprandial syncope by inhibiting the release of GI peptides that
have vasodilator and hypotensive effects.
• The subcutaneous dose ranges from 25 μg bid to 200 μg tid

143. SPECIFIC SYNDROMES OF ANS DYSFUNCTION
MULTIPLE SYSTEM ATROPHY

144. • Multiple system atrophy (MSA) is an entity that comprises autonomic
failure (OH or a neurogenic bladder) and either parkinsonism (MSA-p)
or a cerebellar syndrome (MSA-c).
• MSA-p is the more common form;
• the parkinsonism is atypical in that there is more symmetric motor
involvement than in Parkinson’s disease ,
• tremor is not as prominent, and there is a poor or only transient
response to levodopa.
• Symptomatic OH within 1 year of onset of parkinsonism is suggestive
of MSA-p.

145. MSA
• There is a very high frequency of impotence in men.
• Although autonomic abnormalities are common in advanced PD, the
severity and distribution of autonomic failure are more severe and
generalized in MSA.
• Brain magnetic resonance imaging (MRI) is a useful diagnostic
adjunct: in MSA-p, iron deposition in the striatum may be evident as
T2 hypointensity, and in MSA-c, cerebellar atrophy is present with a
characteristic T2 hyperintense signal (“hot cross buns sign”) in the
pons
• However, these MRI findings are typically present only with advanced
disease

146. (Fig. 432-2).

147. • Cardiac postganglionic adrenergic innervation, measured by uptake of
fluorodopamine on positron emission tomography, is markedly
impaired in the dysautonomia of PD but is usually normal in MSA.
• Neuropathologic changes include neuronal loss and gliosis in many
CNS regions, including the brainstem, cerebellum, striatum, and
intermediolateral cell column of the thoracolumbar spinal cord.

148. • The diagnosis should be considered in adults aged >30 years who
present with OH or urinary incontinence and either parkinsonism that
is poorly responsive to dopamine replacement or a cerebellar
syndrome

149. • Management is symptomatic
• for neurogenic OH ,
• sleep disorders including laryngeal stridor,
• GI, and urinary dysfunction. GI management includes frequent small
meals, soft diet, stool softeners, and bulk agents.
• Gastroparesis is difficult to treat; metoclopramide stimulates gastric
emptying but worsens parkinsonism by blocking central dopamine
receptors.

150. • The peripheral dopamine (D2 and D3 ) receptor antagonist domperidone has
been used patients with various GI conditions in many countries,
• Autonomic dysfunction is also a common feature in dementia with Lewy bodies
with the severity usually intermediate between that found in MSA and PD.

151. • In multiple sclerosis autonomic complications reflect the CNS location
of MS involvement and generally worsen with disease duration and
disability, but are generally a secondary complaint and not of the
severity seen in the synucleinopathies

152. SPECIFIC SYNDROMES OF ANS DYSFUNCTION
SPINAL CORD

153. • Spinal cord lesions from any cause can result in focal autonomic
deficits or autonomic hyperreflexia (e.g., spinal cord transection or
hemisection) affecting bowel, bladder, sexual, temperature-
regulation, or cardiovascular functions.
• Quadriparetic patients exhibit both supine hypertension and OH after
upward tilting. Autonomic dysreflexia describes a dramatic increase in
BP in patients with traumatic spinal cord lesions above the T6 level,
often in response to irritation of the bladder, skin, or muscles.

154. • The triggers may be clinically silent because perception of painful
sensations arising from structures innervated below the level of a
spinal cord lesion is often blunted or absent.
• A distended bladder, often from an obstructed Foley catheter or a
urinary infection, are common triggers of dysreflexia.
• Associated symptoms can include facial flushing, headache,
hypertension, or piloerection.

155. • Potential complications include intracranial vasospasm or
hemorrhage, cardiac arrhythmia, and death.
• In patients with supine hypertension, BP can be lowered by tilting the
head upward or sitting the patient up.
• Vasodilator drugs may be used to treat acute elevations in BP.
Clonidine can be used prophylactically to reduce the hypertension
resulting from bladder stimulation.

156. • Dangerous increases or decreases in body temperature may result
from an inability to sense heat or cold exposure or control peripheral
vasoconstriction or sweating below the level of the spinal cord injury

157. SPECIFIC SYNDROMES OF ANS DYSFUNCTION
PERIPHERAL NERVE AND NEUROMUSCULAR JUNCTION DISORDERS

158. • Peripheral neuropathies are the most common cause of chronic autonomic
insufficiency.
• Polyneuropathies that affect small myelinated and unmyelinated fibers of
the sympathetic and parasympathetic nerves commonly occur in
diabetes mellitus,
amyloidosis,
chronic alcoholism,
porphyria,
and Guillain-Barré syndrome.
• Neuromuscular junction disorders with autonomic involvement include
botulism and Lambert-Eaton syndrome

159. Diabetes Mellitus
• The presence of autonomic neuropathy in patients with diabetes increases
the mortality rate 1.5- to 3-fold, even after adjusting for other
cardiovascular risk factors.
• Estimates of 5-year mortality risk among these patients range from 15 to
53%.
• Although many deaths are due to secondary vascular disease, there are
patients who specifically suffer cardiac arrest due to autonomic
neuropathy.
• The autonomic involvement is also predictive of other complications
including renal disease, stroke, and sleep apnea.
• Tight glycemic control with insulin significantly reduces the long-term risk
of autonomic cardiovascular neuropathy.

160. Amyloidosis
• Autonomic neuropathy occurs in both sporadic and familial forms of
amyloidosis.
• The AL (immunoglobulin light chain) type is associated with primary
amyloidosis or amyloidosis secondary to multiple myeloma.
• The amyloid transthyretin (ATTR) type, with transthyretin as the
primary protein component, is responsible for the most common
form of inherited amyloidosis.
• Although patients usually present with a distal sensorimotor
polyneuropathy accompanied by autonomic insufficiency that can
precede the development of the polyneuropathy or occur in isolation.

161. Amyloidosis ………..cont…….
• The diagnosis can be made by protein electrophoresis of blood and
urine, tissue biopsy (abdominal fat pad, rectal mucosa, or sural nerve)
to search for amyloid deposits,
• and genetic testing for transthyretin mutations in familial cases.
• Death is usually due to cardiac or renal involvement.
• Postmortem studies reveal amyloid deposition in many organs,
including two sites that contribute to autonomic failure: intraneural
blood vessels and autonomic ganglia.
• Pathologic examination reveals a loss of both unmyelinated and
myelinated nerve fibers.

162. Alcoholic Neuropathy
• Abnormalities in parasympathetic vagal and efferent sympathetic function
are usually mild in alcoholic polyneuropathy.
• OH is usually due to brainstem involvement, rather than injury to the PNS.
• Impotence is a major problem, but concurrent gonadal hormone
abnormalities may play a role in this symptom.
• Clinical symptoms of autonomic failure generally appear only when the
stocking-glove polyneuropathy is severe, and there is usually coexisting
Wernicke’s encephalopathy.
• Autonomic involvement may contribute to the high mortality rates
associated with alcoholism

163. Porphyria
• Autonomic dysfunction is most extensively documented in acute
intermittent porphyria but can also occur with variegate porphyria and
hereditary coproporphyria.
• Autonomic symptoms include tachycardia, sweating, urinary retention,
abdominal pain, nausea and vomiting, insomnia, hypertension, and (less
commonly) hypotension.
• Another prominent symptom is anxiety.
• Abnormal autonomic function can occur both during acute attacks and
during remissions.
• Elevated catecholamine levels during acute attacks correlate with the
degree of tachycardia and hypertension that is present.

164. Guillain-Barré Syndrome
• BP fluctuations and arrhythmias from autonomic instability can be
severe.
• It is estimated that between 2 and 10% of patients with severe
Guillain-Barré syndrome suffer fatal cardiovascular collapse.
• GI autonomic involvement, sphincter disturbances, abnormal
sweating, and pupillary dysfunction can also occur.
• Demyelination has been described in the vagus and glossopharyngeal
nerves, the sympathetic chain, and the white rami communicantes.

165. Guillain-Barré Syndrome ……cont…..
• Interestingly, the degree of autonomic involvement appears to be
independent of the severity of motor or sensory neuropathy.
• Acute autonomic and sensory neuropathy is a variant that spares the
motor system and presents with neurogenic OH and varying degrees
of sensory loss.
• It is treated similarly to Guillain-Barré syndrome, but prognosis is less
favorable, with persistent severe sensory deficits and variable degrees
of OH in many patients.

166. Autoimmune Autonomic Ganglionopathy (AAG)
• This disorder presents with the subacute development of autonomic
disturbances including OH, enteric neuropathy (gastroparesis, ileus,
constipation/diarrhea), flaccid bladder, and cholinergic failure (e.g.,
loss of sweating, sicca complex, and a tonic pupil).
• A chronic form of AAG resembles pure autonomic failure (PAF).
• Autoantibodies against the α3 subunit of the ganglionic Ach receptor,
present in approximately half of patients, are considered diagnostic of
AAG.
• Pathology shows preferential involvement of small unmyelinated
nerve fibers, with sparing of larger myelinated ones.

167. Autoimmune Autonomic Ganglionopathy (AAG)
• Pathology shows preferential involvement of small unmyelinated
nerve fibers, with sparing of larger myelinated ones.
• Onset of the neuropathy follows a viral infection in approximately half
of cases.
• Up to one-third of untreated patients experience significant
functional improvement over time.
• Immunotherapies that have been reported to be helpful include
plasmapheresis, intravenous immune globulin, glucocorticoids,
azathioprine, rituximab, and mycophenolate mofetil.

168. Autoimmune Autonomic Ganglionopathy (AAG)
• OH, gastroparesis, and sicca symptoms can be managed
symptomatically.
• AAG can also occur on a paraneoplastic basis, with adenocarcinoma
or small-cell carcinoma of the lung, lymphoma, or thymoma being the
most common.
• Cerebellar involvement or dementia may coexist, and the neoplasm
can be occult.

169. Botulism
• Botulinum toxin binds presynaptically to cholinergic nerve terminals
and, after uptake into the cytosol, blocks ACh release.
• This acute cholinergic neuropathy presents as motor paralysis and
autonomic disturbances that include blurred vision, dry mouth,
nausea, unreactive or sluggishly reactive pupils, constipation, and
urinary retention

170. SPECIFIC SYNDROMES OF ANS DYSFUNCTION
■ PURE AUTONOMIC FAILURE (PAF)

171. PAF
• This sporadic syndrome consists of postural hypotension, impotence, bladder
dysfunction, and impaired sweating.
• The disorder begins in midlife and occurs in women more often than men.
• The symptoms can be disabling, but life span is unaffected.
• The clinical and pharmacologic characteristics suggest primary involvement of
postganglionic autonomic neurons.
• A severe reduction in the density of neurons within sympathetic ganglia results in
low supine plasma NE levels and noradrenergic supersensitivity.

172. PAF
• Some patients who are initially labeled with this diagnosis subsequently go on to
develop AAG, but more often a neurodegenerative disease supervenes, typically
Lewy body dementia, PD, or MSA.
• In one recent series, more than one-third of patients initially diagnosed with PAF
developed a CNS synucleinopathy within 4 years, and the presence of rapid eye
movement sleep behavior disorder was predictive of subsequent CNS disease.
• Skin biopsies and autopsy studies demonstrate phosphorylated α-synuclein
inclusions in postganglionic sympathetic adrenergic and cholinergic nerve fibers,
distinguishing PAF from AAG
• and indicating that PAF is a synucleinopathy; notably, patients with PD also have
α-synuclein inclusions in sympathetic nerve biopsies

173. SPECIFIC SYNDROMES OF ANS DYSFUNCTION
POSTURAL ORTHOSTATIC TACHYCARDIA SYNDROME (POTS)

174. POTS
• This syndrome is characterized by symptomatic orthostatic intolerance without
OH, accompanied by either an increase in heart rate to >120 beats/min or an
increase of 30 beats/min with standing that subsides on sitting or lying down.
• Women are affected approximately five times more often than men, and most
develop the syndrome between the ages of 15 and 50.
• Presyncopal symptoms (lightheadedness, weakness, blurred vision) combined
with symptoms of autonomic overactivity (palpitations, tremulousness, nausea)
are common.

175. POTS
• The pathogenesis is typically multifactorial which frequently confounds the
clinical picture
• A number of potential causes have been reported, including sympathetic
denervation distally in the legs with preserved cardiovascular function or reduced
cardiac function due to deconditioning.
• Hypovolemia, venous pooling, impaired brainstem baroreceptor regulation, or
increased sympathetic activity may also play a role.
• No standardized approach to diagnosis has been established, and therapy
typically has included symptomatic relief with a focus on cardiovascular
rehabilitation, including a sustained exercise program.

176. POTS
• Expansion of fluid volume with water, salt, and fludrocortisone can be helpful as
an initial intervention.
• In some patients, low-dose propranolol (20 mg) provides a modest improvement
in heart rate control and exercise capacity.
• If these approaches are inadequate, then midodrine, pyridostigmine, or clonidine
can be considered

177. SPECIFIC SYNDROMES OF ANS DYSFUNCTION
INHERITED DISORDERS

178. Five hereditary sensory and autonomic
neuropathies (HSANs)
• Five hereditary sensory and autonomic neuropathies (HSANs) exist, designated
HSAN I–V.
• The most important autonomic variants are HSAN I and HSAN III.
• HSAN I is dominantly inherited and often presents as a distal small-fiber
neuropathy (burning feet syndrome) associated with sensory loss and foot ulcers.
• The most common responsible gene, on chromosome 9q, is SPTLC1. SPTLC is a
key enzyme in the regulation of ceramide.
• Cells from HSAN I patients with the mutation produce higher-than-normal levels
of glucosyl ceramide, perhaps triggering apoptosis.

179. Five hereditary sensory and autonomic neuropathies
(HSANs) …..cont…..
• HSAN III (Riley-Day syndrome; familial dysautonomia) is an autosomal
recessive disorder of Ashkenazi Jewish children and adults and is
much less prevalent than HSAN I.
• Decreased tearing, hyperhidrosis, reduced sensitivity to pain,
areflexia, absent fungiform papillae on the tongue, and labile BP may
be present.
• Individuals with HSAN III have afferent, but not efferent, baroreflex
failure that causes the classic episodic abdominal crises and blood
pressure surges in response to emotional stimuli.

180. Five hereditary sensory and autonomic neuropathies
(HSANs) …..cont…..
• Pathologic examination of nerves reveals a loss of sympathetic,
parasympathetic, and sensory neurons.
• The defective gene, IKBKAP, prevents normal transcription of important
molecules in neural development

181. SPECIFIC SYNDROMES OF ANS DYSFUNCTION
HYPERHIDROSIS

182. • This syndrome presents with excess sweating of the palms of the
hands and soles of the feet beginning in childhood or early
adulthood.
• The condition tends to improve with age.
• The disorder affects 0.6–1.0% of the population.
• The etiology is unclear, but there may be a genetic component
because 25% of patients have a positive family history.

183. • The condition can be socially embarrassing (e.g., shaking hands) or
even disabling (e.g., inability to write without soiling the paper).
• Topical antiperspirants are occasionally helpful.
• More useful are potent anti-cholinergic drugs such as glycopyrrolate
1–2 mg PO tid or oxybutynin 5 mg po bid.
• T2 ganglionectomy or sympathectomy is successful in >90% of
patients with palmar hyperhidrosis.

184. • The advent of endoscopic transaxillary T2 sympathectomy has lowered the
complication rate of the procedure.
• The most common postoperative complication is compensatory
hyperhidrosis, which improves spontaneously over months.
• Other potential complications include recurrent hyperhidrosis (16%),
Horner’s syndrome (<2%) , gustatory sweating, wound infection,
hemothorax, and intercostal neuralg

185. • Local injection of botulinum toxin has also been used to block
cholinergic, postganglionic sympathetic fibers to sweat glands.
• This approach is effective but limited by the need for repetitive
injections (the effect usually lasts 4 months before waning).

186. SPECIFIC SYNDROMES OF ANS DYSFUNCTION
ACUTE SYMPATHETIC OVERACTIVITY SYNDROMES

187. Autonomic storm
• An autonomic storm is an acute state of sustained sympathetic surge
that results in variable combinations of alterations in BP and heart
rate, body temperature, respiration, and sweating.
• Causes of autonomic storm include brain and spinal cord injury, toxins
and drugs, autonomic neuropathy, and chemodectomas (e.g.,
pheochromocytoma).
• Brain injury is the most common cause of autonomic storm and
typically follows severe head trauma and postresuscitation anoxic-
ischemic brain injury.

188. Autonomic storm
• Autonomic storm can also occur with other acute intracranial lesions such
as hemorrhage, cerebral infarction, rapidly expanding tumors,
subarachnoid hemorrhage, hydrocephalus, or (less commonly) an acute
spinal cord lesion.
• The most consistent setting is that of an acute intracranial
catastrophe of sufficient size and rapidity to produce a massive
catecholaminergic surge

189. Autonomic storm
• The surge can cause seizures, neurogenic pulmonary edema, and
myocardial injury.
• Manifestations include fever, tachycardia, hypertension, tachypnea,
hyperhidrosis, pupillary dilatation, and flushing.
• Lesions of the afferent limb of the baroreflex can result in milder
recurrent autonomic storms; these can be associated with tumors or
follow neck irradiation or surgery that damages the vagus and
glossopharyngeal nerves

190. Autonomic storm
• Drugs and toxins may also be responsible, including
sympathomimetics such as phenylpropanolamine, cocaine,
amphetamines, and tricyclic antidepressants; tetanus; and, less often,
botulinum toxin.
• Cocaine, including “crack,” can cause a hypertensive state with CNS
hyperstimulation.
• An overdose of tricyclic antidepressants, such as amitriptyline, can
cause flushing, hypertension, tachycardia, fever, mydriasis, anhidrosis,
and a toxic psychosis.

191. Autonomic storm
• The hyperadrenergic state associated with Guillain-Barré syndrome can
produce a moderate autonomic storm.
• Pheochromocytoma presents with a paroxysmal or sustained
hyperadrenergic state, headache, hyperhidrosis, palpitations, anxiety,
tremulousness, and hypertension.

192. Neuroleptic malignant syndrome
• Neuroleptic malignant syndrome refers to a syndrome of muscle
rigidity, hyperthermia, and hypertension in patients treated with
neuroleptic agents
• (including lower potency and atypical antipsychotic agents, and even
antiemetic drugs such as metoclopramide, promethazine)
• Management of autonomic storm includes ruling out other causes of
autonomic instability, including malignant hyperthermia, porphyria,
and seizures.

193. Neuroleptic malignant syndrome
• Sepsis and encephalitis need to be excluded with appropriate studies.
• An electroencephalogram (EEG) should be done to search for seizure activity; MRI
of the brain and spine is often necessary.
• The patient should be managed in an intensive care unit.
• Management with morphine sulphate (10 mg every 4 h) and labetalol (100–200
mg twice daily) may be helpful.
• Supportive treatment may need to be maintained for several weeks. For chronic
and milder autonomic storm, propranolol and/or clonidine can be effective.

194. SPECIFIC SYNDROMES OF ANS DYSFUNCTION
MISCELLANEOUS

195. • Other conditions associated with autonomic failure include
infections,
malignancy,
and poisoning (organophosphates).
• Disorders of the hypothalamus can affect autonomic function and produce
abnormalities
in temperature control,
satiety,
sexual function,
and circadian rhythms

196. SPECIFIC SYNDROMES OF ANS DYSFUNCTION
COMPLEX REGIONAL PAIN SYNDROMES (CRPS)

197. CRPS
• The failure to identify a primary role of the ANS in the pathogenesis
of these disorders has resulted in a change of nomenclature.
• The terms CRPS types I and II are now used in place of reflex
sympathetic dystrophy (RSD) and causalgia.
• CRPS type I is a regional pain syndrome that often develops after
tissue injury and most commonly affects one limb.

198. CRPS type I
• Examples of associated injury include minor shoulder or limb trauma, fractures,
myocardial infarction, or stroke.
Allodynia (the perception of a nonpainful stimulus as painful),
hyperpathia (an exaggerated pain response to a painful stimulus),
and spontaneous pain occur.
• The symptoms are unrelated to the severity of the initial trauma and are not
confined to the distribution of a single peripheral nerve.

199. CRPS type II
• CRPS type II is a regional pain syndrome that develops after injury to a specific
peripheral nerve, often a major nerve trunk.
• Spontaneous pain initially develops within the territory of the affected nerve but
eventually may spread outside the nerve distribution.
• Although CRPS type I (RSD) has been classically divided into three clinical phases,
there is little evidence that CRPS “progresses” from one stage to another.

200. CRPS type II
• Currently, the Budapest consensus criteria for clinical diagnosis of CRPS delete
staging and require at least three symptoms and two signs in the following four
categories:
• (1) sensory, (2) vasomotor, (3) sudomotor/edema, and (4) motor/trophic.
• Pain (usually burning or electrical in quality) is the primary clinical feature of
CRPS.
• Limb pain syndromes that do not meet these criteria are best classified as “limb
pain—not otherwise specified.”

201. CRPS…..cont….
• In CRPS, localized sweating (increased resting sweat output) and changes in blood
flow may produce temperature differences between affected and unaffected
limbs.
• The natural history of typical CRPS may be more benign and more variable than
previously recognized.
• A variety of surgical and medical treatments have been developed, with
conflicting reports of efficacy.

202. CRPS…..cont….
• Clinical trials suggest that early mobilization with physical therapy or a
brief course of glucocorticoids may be helpful for early CRPS type I or
II.
• Chronic glucocorticoid treatment is not recommended.
• Current treatment paradigms are multidisciplinary with a focus on early
mobilization, physical therapy, pain management, patient education, and
psychological support.