Autonomic function testing21.4.2015

Autonomic dysfunction can occur as a result of many diseases that affect autonomic pathways.

The clinician’s role is to seek out symptoms of dysautonomia

Necessary to determine if these symptoms are really due to involvement of autonomic systems.

The conceptual framework began 19th century .

These original tests were developed over time .

Widely used in clinical practice for 50 years Decades of extensive experience and

thousands of studies published on its use.

Introduction

1. To evaluate the severity and distribution of autonomic function

2. To diagnose limited autonomic neuropathy

3. To diagnose and evaluate orthostatic intolerance

4. To monitor the course of dysautonomia5. To monitor response to treatment6. As an instrument in research studies

Clinical goals in the evaluation of autonomic function

1. Cardiovagal innervation (parasympathetic

innervation): heart rate (HR) response to deep breathing, Valsalva ratio, and HR response to standing (30:15 ratio)

2. Adrenergic: beat-to-beat blood pressure (BP) responses to the Valsalva maneuver, sustained hand grip, and BP and HR responses to tilt-up or active standing

3. Sudomotor: quantitative sudomotor axon reflex test (QSART), thermoregulatory sweat test (TST), sympathetic skin response (SSR).

Tests

Beat to beat heart rate analysisHeart rate documented on ECG or on EMG

equipmentFor ECG in EMG Low filter 1-5 Hz; High filter 500HzSlow oscilloscope sweep time(0.2-1 secs)Sensitivity- 0.5 mvActive electrode midline posteriorly between

inferior angle of scapula; reference mid axillary line

Heart rate and BP recording

Heart rate is inversely related to RR intervalHeart rate(R-R/min)= sweep speed(mm/s)÷RR interval x60BP sphygmomanometerBeat to beat BP measurement formerly

required invasive intra arterial measurement; but plethysmography

The variation of heart rate with respiration is known as sinus arrhythmia

Inspiration increases the heart rateExpiration decreases the heart rate

This is also called Respiratory Sinus Arrhythmia (RSA)

This is an index of vagal control of heart rate

1. Heart rate variation during respiration

Sinus Arrhythmia

Due to changes in vagal control of heart rate during respiration

Probably due to following mechanisms Influence of respiratory centre on the vagal

control of heart rate Influence of pulmonary stretch receptors on the

vagal control of heart rate

Explanation for sinus arrhythmia

Connect the ECG electrodes for recording lead II

Ask the subject to breath deeply at a rate of

six breaths per minute for 3 cycles(allowing 5 seconds each for inspiration and expiration)

Procedure

Deep breathing

Record maximum and minimum heart rate with each respiratory cycle

Average the 3 differences

Normal > 15 beats/minBorderline = 11-14 beats/minAbnormal < 10 beats/min

Procedure

Determine the expiration to inspiration ratio (E:I ratio)

Mean of the maximum R-R intervals during deep expiration to the mean of minimum R-R intervals during deep inspiration

Procedure

longest RR interval (expiration)

Ratio = -------------------------------------

shortest RR interval (inspiration)

E:I = 1.2

E:I ratio

An immediate response with an abrupt fall in systolic and diastolic blood pressure and a visible acceleration of heart rate (first 30 s),

a phase of early stabilization, which occurs after approximately 1-2 min,

a response to prolonged orthostasis lasting for more than 5 min.

during the phase of stabilization , acceleration of heart rate by about 10-15 beats per minute and a slight decrease in systolic blood pressure, while diastolic pressure increases by approximately 10 mmHg

2. Heart rate variation during postural change

Evaluation of changes in heart rate (30/15 ratio) is performed during the initial phase of adaptation to orthostasis .

On standing the heart rate increases until it reaches a maximum at about

15th beat (shortest R-R interval after standing)after which it slows down to a stable state at

about 30th beat (longest R-R interval after standing)

Heart rate variation during postural change

Heart rate response to standing from supine posture

The ratio of R-R intervals corresponding to the 30th and 15th heart beat 30:15 ratio

RR interval at 30th beat30:15 ratio = ------------------------------

RR interval at 15th beat

This ratio is a measure of parasympathetic response

30:15 ratio

RR interval at 30th beat30:15 ratio =

------------------------------ RR interval at 15th beat

Normal > 1.04Borderline = 1.01-1.04Abnormal =<1.00

30:15 ratio

Fluctuations of blood pressure are assessed based on somewhat later responses to standing (first 4 min)

they are expressed as the difference between the baseline supine and the minimal blood pressure after standing up.

A decline in systolic blood pressure by more than 20 mmHg and by more than 10 mmHg for diastolic blood pressure is considered abnormal

OH- fall of 20 mm Hg systolic or 10 mm Hg diastolic BP on standing- AAS ;AAN 1996

30mmHg systolic; 20 mmHg diastolic BP- McLeod and Tuck, 1987

Diagnostic criteria of POTS include a) a sustained increase in heart rate (HR) of

30 beats per minute (bpm) or greater during 10 minutes of assuming an upright position,

b) no associated hypotension, and c) symptoms of orthostatic intolerance,

which must be present for at least three months.

In severe forms of the disease, HR may increase to more than 120 bpm on standing.

Assesses integrity of the baroreceptor reflex

Measure of parasympathetic and sympathetic function

It is “forced expiration against a closed glottis”

3. Valsalva Manoeuvre

The Valsalva maneuver is performed by attempting to forcibly exhale while keeping the mouth and nose closed

It increases intrathoracic pressure to as much as 80 mmHg

Valsalva Manoeuvre

Perform the Valsalva manoeuvre (forced expiration against a closed glottis) by asking the subject to breathe forcefully into a mercury manometer and maintain a pressure of 40 mmHg for 15 seconds

Record the ECG throughout and for 30 seconds after the procedure

Procedure

4 phasesPhase IPhase IIPhase IIIPhase IV

Valsalva Manoeuvre

Four Phases

Transient increase in BP which lasts for a few seconds HR does not change much Mechanism: increased intrathoracic pressure and mechanical

compression of great vessels due to the act of blowing

Phase I – Onset of straining

Early part – drop in BP lasting for about 4 seconds

Latter part – BP returns to normalHeart rate rises steadily

Phase II - Phase of straining

Mechanism

Early partvenous return decreases with compression of veins

by increased intrathoracic pressure central venous pressure decreases BP decreases

Latter partdrop in BP in early part will stimulate baroreceptor

reflex increased sympathetic activity increased peripheral resistance increased BP ( returns to normal )

Heart rate increase steadily throughout this phase due to vagal withdrawal in early part & sympathetic activation in latter part

Transient decrease in BP lasting for a few seconds

Little change in heart rate

Phase III - Release of straining

Mechanical displacement of blood into pulmonary vascular bed, which was under increased intrathoracic pressure BP decreases

Mechanism

BP slowly increases and heart rate proportionally decreases

BP overshootsOccurs 15-20 s after release of strain and lasts for

about a minute or more

Phase IV – further release of strain

Due to increase in venous return, stroke volume and cardiac output

Mechanism

¨ Phase I Increase in BP

¨ Phase II Decrease in BP, Tachycardia

¨ Phase III Decrease in BP

¨ Phase IV Overshoot of BP, Bradycardia

Phases

Measure of the change of heart rate that takes place during a brief period of forced expiration against a closed glottis

Ratio of longest R-R interval during phase IV (within 20 beats of ending maneuver) to the shortest R-R interval during phase II

Average the ratio from 3 attempts

Valsalva Ratio

Longest RR

Valsalva Ratio = -----------------------------

Shortest RR

Values :> 1.4more than 1.21 normalless than 1.20 abnormal

Valsalva Ratio

Valsalva maneuver evaluates1. sympathetic adrenergic functions using the

blood pressure responses 2. cardiovagal (parasympathetic) functions using

the heart rate responses 

Valsalva manoeuvre

4. Cold pressor testSubmerge the hand in ice cold water(1

minute)

diastolic pressure by >15 mmHgHR>10/min

5. Isometric handgrip test isometric pressing of a handgrip dynamometer

at approximately one third of the maximum contraction strength for 3-5 min.

Blood pressure measurements are taken at the other arm at 1 min interval

Rise of DBP>15/min

Tilt table test

• Patient refusal• Morbid obesity (technicians cannot tilt

safely)• Unable to stand for long periods due to pain• Pregnancy• Recent (within 6 months) myocardial

infarction or stroke/TIA• A known tight stenosis anywhere (eg heart

valve, LV outflow obstruction, coronary or carotid/cerebrovascular artery)

Contraindications

Fast 2 or more hrsRest supine 20-45 minutesStop drugs affecting cvs or autonomic

function; minimum of 5 half life pretestMinimize lower limb movementsGet the baseline blood pressure from the

brachial artery. Acquire the 5-10 minutes baselineTilt angle and duration

Method

Tilt patient up. The tilt should be done at 70 degree. The transition from supine to tilt position should smooth and of duration 5-10 seconds.

Obtain the blood pressure from a brachial artery every minute.

Observe subject for the presence of any discomfort, chest pain, shortness of breath, dizziness, lightheadedness, syncope

Be prepared to terminate the tilt of any serious event occurs during the tilt based on clinical judgment.

The tilt can be continued if no obvious abnormalities are detected but a clinical history is strongly suggestive of dysautonomia or blood pressure instability.

Tilt the patient back.

Method

The normal responses in heart rate during the tilt is heart rate increment within 10 - 15 beats per minute.

At the same time the maximal heart rate should be less than 120 beats per minute.

Normal responses in the blood pressure during the tilt modest rise of diastolic blood pressure ; slight fall of <10 mm Hg in SBP.

PHYSIOLOGICAL BASIS OF HUT

From studies HUT testing (2 occasions), with a known time interval,an average reproducibility of 81%

However, as Behzad and collaborators and other authors

highlighted, negative results are much more reproducible than positive ones (about 95% and 50% respectively).

depends strongly on population selection as it is increased in patients with severe and frequent orthostatic symptoms.

Reproducibility

Studies assessing the ability of the HUT test to diagnose neurocardiogenic syncope averaged a sensitivity of 35% without pharmacologic stimulation

57% with pharmacologic stimulationStudies using HUT testing within the

boundaries set by the American College of Cardiology guidelines averaged a sensitivity of 65%

The specificity of the HUT test for neurocardiogenic syncope 92% on average without pharmacologic stimulation

81% with pharmacologic stimulation Two investigator-HUT test-American College

of Cardiology guidelines-both yielded a specificity of 100%.

TST

Thermoregulatory sweat testing (TST) is used evaluate the integrity of central and

peripheral sympathetic sudomotor pathways from the CNS to the cutaneous sweat glands

The temperature is adjusted to 45–50 °C with a relative humidity of 35–40%.

Sweat produces a change in local pH resulting in the indicator dye changing color

marking the location of sweat production (sweat has a pH of 4.5–5.5 at low sweat rates of 15–100nL/gland per hour).

Two common indicators include alizarin red powder (alizarin red, corn starch, sodium carbonate, 1:2:1) and iodine corn starch.

Maximal sweating is achieved within 30–65 minutes.

Heating time should not exceed 70 minutes to avoid hyperthermia

Sweating causes the indicator to change its color (from yellow to dark red for alizarin red and from brown to purple with iodine).

Digital photographs are taken and a sweat density map is generated on standard anatomical drawings

Data are expressed as TST% which is the measured area of anhidrosis divided by the area of the anatomic figure, multiplied by 100

Normal sweating patterns are generally symmetric but vary in quantity

Asymmetric sweat patterns and anhidrotic areas (focal, segmental, regional, length dependent) are noted.

The TST% can provide a general index of severity of the autonomic failure

LimitationsTST can localize specific areas of sudomotor

dysfunction but can not differentiate preganglionic from postganglionic lesions

In combination with a test measuring postganglionic sudomotor function (QSART, silicone impression) the site of a lesion can be separated:

preganglionic lesions show an abnormal TST, while the QSART, or silicone imprints are normal.

A postganglionic lesion will be abnormal in all tests

Quantitative sudomotor axon reflex test (QSART) is used to evaluate postganglionic sympathetic cholinergic sudomotor function

Axon-reflex mediated sweat response over time and has achieved widespread clinical use.

Quantitative sudomotor axon reflex test (QSART)

Clean the recording sites vigorously with the alcohol.

Recording sites are:1) the medial forearm (75 % distance from the ulnar epicondyle to the pisiform bone);

2) the proximal leg (5 cm distal to the fibular head laterally);

3) the distal leg (5 cm proximal to the medial malleolus medially

4) proximal foot over the extensor digitorum brevis muscle.

Place the ground for stimulation about 5 cm next to the capsule.

METHODOLOGY

Wait until the baseline sweat is flat, below 100 nanoliters/minute and all channels give similar baseline sweat output (difference < 15 %,)

Start stimulation at current 2 mA for 5 minutes, turn on the marker.

Record another 5 minute of the sweat (total 10 minutes), turn on the marker.

Obtain the latencies and volumes at each site

Stable baseline of spontaneous sweating

In normal individuals, the sweat output starts with a delay of 1–2 minutes.

The sweat output increases for up to 5 minutes after stimulation until it reaches the inflection point and decreases slowly.

While males and females have similar latency the sweat output differs.

Mean sweat output for males is 2–3 μl/cm2 (approximate range 0.7–5.4 μl/cm2) and

females 0.25–1.2 μl/cm2 (approximate range 0.2–3 μl/cm2) with some variation depending on the site of stimulation

Sweat response can be absent, decreased or increased.

longer latency of the sweat onset can be seen as well as a lack of recovery, the “hung up” response

Increased sweat production is often a sign of axonal excitability,

seen in conditions such as diabetic neuropathy, reflex sympathetic dystrophy and other small fiber neuropathies.

In diabetic neuropathy, especially during early stages, a length-dependent pattern of sweat reduction can be seen

QSART measures the postganglionic sudomotor response and will be unable to detect preganglionic lesions.

QSART is also time-consuming, requires special equipment and is not widely available

Limitations

SSR, also referred to as galvanic skin response is a measure of electrodermal activity

Generated in deep layer of skinReflex activation of sweat glands via

cholinergic sudomotor sympathetic efferent fibres.

Provides a surrogate measure of sympathetic cholinergic sudomotor function.

Sympathetic skin response (SSR)

Historical aspects(SSR) is a change in skin potential following

arousal stimulation, described by Tarchanoff (1890).

Method introduced by Sahani in 1984 and later by Knezevic and Bjada

SSR is a change in potential recorded from surface of skin, representing sudomotor activity

Can be evoked by different stimuliAcoustic; TMS C7, brain; startle; laser skin;

reflex hammer percussion on sternumResende et al deglutition; blinking; skeletal

movements; biting; light stimuli; vocalization; sphincteric contraction

Stimulus modality determine the afferent tract

Electrical stimulation of

peripheral nerve activates afferent

part of reflex consisting thick

myelinated sensory

fibres(typeII)

sensory spinal cord tract

brain stem(influenced

by hypothalamus, medial and basal part of frontal lobe and medial part of temporal

lobe

Afferent tract

originate from the

hypothalamus and descend uncrossed along the

lateral column of the spinal cord to form a small

bundle between the pyramidal

tract and the anterior-

lateral tract. Terminates

on sympathetic

preganglionic neurons in

the intermediolat

eral cell column.

Myelinated sympathetic fibres from intermediol

ateral nucleus in T1- L2 of

spinal cord

Paravertebral

sympathetic ganglia

Post ganglionic

by non myelinated(

type c); innervating sweat gland

Efferent tract

Room temperature should be comfortable and the skin surface temperature 32@C.

potentials are increased during psychological stress and may contaminate the evoked SSR.

situation during recording has to be relaxed, without acoustic disturbances

Technical requirements

Recording is done from glabrous skin and is referenced against hairy skin whose sweat glands are not typically active at normal ambient temperatures.

The surface Ag-AgCl electrodes are placed on the palm (active) and referenced against the volar forearm or dorsum of the hand (indifferent);

and on the sole of the foot (active) and referenced against the shin or dorsum of the foot (indifferent)

Recording

The recording time should be 5±10 s, the lower frequency limit 0.1±2 Hz (better,1

Hz), and the upper limit 100±2000 Hz (not critical).

Amplification should be 0.05±3 mV/division.

Electrical stimulation is carried out with a constant current stimulus (0.2 ms, supramaximal, 10±30 mA).

Typically the median, posterior tibial, peroneal, sural or supraorbital nerves are stimulated at a strength at least three times the sensory threshold.

it is applied at irregular time intervals and at a frequency of approximately 1/min to avoid habituation.

If electrical stimulation at one site does not evoke an SSR, other sites of stimulation should be tried

If the response to electrical stimulation is absent

response to acoustic stimuli or to an inspiratory gasp should be tried (Shahani et al. 1984).

In normal subjects, transcranial magnetic stimulation of the motor strip

elicited palmar and plantar SSRs similar both in latency and amplitude to those

evoked by median nerve stimulation. Normal resultsThe shape of the SSR is variable. The shortest latency to onset and the

maximum peak to trough amplitude of at least 5 recordings is used.

LatencyThe latency of the SSR includes1. afferent conduction (about 20 ms),

2.central processing time (a few milliseconds), 3.and efferent conduction in pre- and slow conducting postganglionic autonomic

nerve.

The mean conduction velocity of sudomotor nerve fibers is about 1±2 m/s.

Conduction in post- ganglionic C fibers as well as activation time of sweat glands include about 95% of the SSR latency

of around 1.5 s at the hands and 2 s at the feet.

differences in fast afferent conduction are not relevant for the SSR latency and the site of stimulation is also not significant

Amplitude Measurements in theory should reflect the density of spontaneously activable sweat glands.

interaction of the two components, sweat gland and epidermal, makes the absolute amplitude of the evoked EDA difficult to interpret.

the reproducibility of the electri-cally evoked SSR is poor.

Age- latency; amplitudeSSR evoked by an auditory stimulus has less

inter and intrasubject latency and waveform variability than the inspiratory gasp induced response.

Still no consensus about the evaluation and processing

Qualitative evaluation accepts only the absence of SSR as a pathological sign

Quantitative evaluation- different opinion

SSR is a poor test of sympathetic sudomotor function.

No close correlation between presence or absence of SSR and the severity of autonomic dysfunction.

polyneuropathy, erectile dysfunction, central degenerative diseases, multiple sclerosis(50%), brain infarction, reflex sympathetic dystrophies, spinal and peripheral nerve lesions.

Diagnostic application

ASSESSMENT: CLINICAL AUTONOMIC TESTING Report of the Therapeutics and Technology Assessment Subcommittee of the American Academy of Neurology AAN 1996

Distal small fiber neuropathySympathetic sudomotor fibers are affected, so

that QSART will show abnormalities at the feet and normal sweating more proximally

thermoregulatory sweat test shows anhidrosis that is confined to the distal feet

confined or becomes generalized. diabetes or amyloidosis can start with DSFN

and progress, while others do not

Applications of Autonomic Testing

e.g: Autonomic neuropathies and multiple system atrophy.

widespread loss of sweating, cardiovagal failure is present, and OH with impaired baroreflexes is seen

Generalized autonomic failure

chronic idiopathic anhidrosis, gastroparesis

Selective autonomic failure

Recent studies indicate that MSA is distinguishable from PD using autonomic tests.

PD is characterized by a length-dependent involvement of postganglionic sudomotor fibers

MSA is characterized by widespread, early and preganglionic autonomic failure.

MIBG or fluorodopa scan of the heart, which images postganglionic adrenergic innervation, is typically defective in PD and normal in MSA

The synucleinopathies

PD case showed very distal anhidrosis, affecting only parts of the toes, and did not progress over time.

In contrast, MSA causes widespread anhidrosis.

If both QSART and TST are performed, normal QSART volume in an anhidrotic region indicates that the lesion is preganglionic in site.

Plasma norepinephrine measured with the subject supine and after a period of standing provides another method of studying adrenergic function.

A normal response consists of doubling of NE on standing.

The patient with generalized postganglionic adrenergic failure, as in pure autonomic failure (PAF), will have low supine NE.

The patient with preganglionic lesion, as in MSA, will typically have normal supine values (since the postganglionic fibers are intact) but a failure to increment on standing

Mishra and kalita: clinical neurophysiologyD. Clausa,* and R. Schondorf: Sympathetic

skin response; 1999 International Federation of Clinical Neurophysiology.

Kucera p, Goldenberg Z, Kurca E: SSR: Review of method and its clinical use;Bratis1 Lek Listy 2004

Ben M.W. Illigens, MD and Christopher H. Gibbons, MD MMSc:Sweat testing to evaluate autonomic function; Clin Auton Res. 2009 April

Peter Novak:Video Article Quantitative Autonomic Testing; 2011 Journal of Visualized Experiments

References

Thanks