Disorders of Autonomic Nervous System

Zubair Sarkar

Anatomic Organization

• Autonomic nervous system consists of

Parasympathetic nervous systemSympathetic nervous system

• The activity of ANS is regulated by central neurons which post integration of afferent information adjust the autonomic outflow according to the need.

• The preganglionic neurons of the parasympathetic nervous system leave CNS in the third, seventh, ninth, and tenth cranial nerves as well as the second and third sacral nerves.

• The preganglionic neurons of the sympathetic nervous system exit the spinal cord between the first thoracic and the second lumbar segments.

• The preganglionic fibres are thinly myelinated

• The postganglionic neurons, located in ganglia outside the CNS, give rise to the postganglionic unmyelinated autonomic nerves that innervate organs and tissues throughout the body.

• Acetylcholine (ACh) is the preganglionic neurotransmitter for both divisions of the ANS as well as the postganglionic neurotransmitter of the parasympathetic neurons

• Norepinephrine (NE) is the neurotransmitter of the postganglionic sympathetic neurons, except for cholinergic neurons innervating the eccrine sweat glands.

• Purinergic fibers may play a role in the control of vasomotor tone and in the regulation of regional blood flow.

• Responses to sympathetic and parasympathetic stimulation are frequently antagonistic reflecting highly coordinated interactions within the CNS.

Autonomic control of BP and HR

• Arterial blood pressure is directly proportional to both vascular resistance and cardiac output; it is maintained within a narrow range by the baroreflex mechanisms

• Vasomotor tone, which determines peripheral resistance, is controlled by the sympathetic nervous system through a group of neurons in the ventrolateral medulla that project to the intermediolateral column(ILC).

• The baroreceptors in the carotid sinus and aortic arch are sensitive to transient blood pressure changes and maintain the systemic blood pressure at a relatively constant level.

• When the blood pressure falls, there is a reduction in the frequency of impulses from the baroreceptors to the nucleus tractus solitarius and other brainstem centers.

• The reflex increase in sympathetic activity causes an increase in the vasomotor tone. The corresponding decrease in vagal efferent activity to the heart causes an increase in the heart rate.

• Sympathetic nerve fiber activity in muscles increases in response to

a fall in blood pressure to changes in posture from the lying to sitting and

standing positions and to the application of negative pressure to the lower body,

which is thought to unload intra thoracic low-pressure volume receptors.

• The splanchnic vascular bed plays an important part in the regulation of blood pressure in humans. There is a marked decrease in mesenteric blood flow

on assuming the upright posture or

on applying negative pressure to the lower body

Autonomic Control of Sweat Glandsand Skin Blood Vessels

• The sweat glands postganglionic sympathetic cholinergic fibers and vasoactive intestinal peptide (VIP)-containing fibers

• Skin blood vessels postganglionic sympathetic noradrenergic fibers.

• The sudomotor fibers are faster conductors than the vasomotor fibers.

• Muscle and skin sympathetic activity differ in their responses to a range of stimuli.

• Skin sympathetic activity, in contrast to muscle sympathetic activity, is increased by mental stress and emotional stimuli and cooling, but not significantly by the Valsalva maneuver or body posture.

Classification I. Diseases affecting central nervous systemA. Progressive autonomic failure (PAF) (idiopathicorthostatic hypotension)1. Pure PAF2. PAF with parkinsonian features(PAF-P)3. PAF with multiple-system atrophy (Shy-Dragersyndrome)(PAF-MSA)

B. Parkinson’s diseaseC. Spinal cord lesionsD. Wernicke’s encephalopathy

E. Miscellaneous diseases

1. Cerebrovascular disease2. Brainstem tumors3. Multiple sclerosis4. Adie’s syndrome5. Tabes dorsalis

II.Diseases affecting the peripheral autonomic nervous system

A. Disorders with no associated peripheral neuropathy

1. Acute and subacute autonomic neuropathya. Pandysautonomiab. Cholinergic dysautonomia

2. Botulism

B. Disorders associated with peripheral neuropathy

1. Autonomic dysfunction clinically important

a. Diabetesb. Amyloidosisc. Acute inflammatory neuropathyd. Acute intermittent porphyriae. Familial dysautonomia (Riley-Day syndrome)f. Chronic sensory and autonomic neuropathy

2. Autonomic dysfunction usually clinically not important

a. Alcohol-induced neuropathyb. Toxic neuropathies c. Malignancyd. Vitamin B12 deficiencye. Rheumatoid arthritisf. Chronic renal failureg. Systemic lupus eryrhematosush. Mixed connective tissue diseasei. Fabry’s diseasej. Chronic inflammatory neuropathy

Symptoms of Dysautonomia

• orthostatic hypotension• syncope• sleep dysfunction• altered sweating (hyperhidrosis or hypohidrosis) • constipation• upper gastrointestinal symptoms (bloating, nausea, vomiting

of old food)• impotence or • bladder disorders (urinary frequency, hesitancy, or

incontinence)

Tests for Dysautonomia

Heart Rate Variation with Deep Breathing

• parasympathetic component (vagus nerve) of cardiovascular reflexes.

• Influenced by multiple factors subject’s position (recumbent, sitting or standing) rate and depth of respiration 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.

• For example, the lower limit of normal heart rate variation with deep breathing in persons <20 years is 15–20 beats/min, but for persons over age 60 it is 5–8 beats/min.

• Rate variation with deep breathing (respiratory sinus arrhythmia) is abolished by the muscarinic acetylcholine (ACh)-receptor antagonist atropine but is unaffected by sympathetic postganglionic blockade (e.g., propranolol)

Valsalva Response

• Assesses integrity of the baroreflex control of heart rate (parasympathetic) and BP (adrenergic).

• Tested in the supine position.

• The subject exhales against a closed glottis for 15s.

• Autonomic function during the Valsalva maneuver can be measured using beat-to-beat blood pressure or heart rate changes.

Sudomotor Function

• Sweating is induced by release of Ach from sympathetic postganglionic fiber.

• 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).

• The thermoregulatory sweat test (TST) is a qualitative measure of regional sweat production in response to an elevation of body temperature under controlled conditions.

• An indicator powder (alizarin red powder or iodine corn starch) changes color with sweat production during temperature elevation. The pattern of color change is a measure of regional sweat secretion.

• A postganglionic lesion is present if both QSART and TST show absent sweating.

• In a preganglionic lesion, QSART is normal but TST shows anhidrosis.

Orthostatic BP Recordings

• Beat-to-beat BP measurements determined in supine, 70° tilt, and tilt-back positions.

• The BP change combined with heart rate monitoring is useful for the evaluation of patients with suspected OH or unexplained syncope

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, angle and duration of tilt, and procedure for provocation of vasodilation (e.g., sublingual or spray nitroglycerin).

Treatment

• 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.

PATIENT EDUCATION

• Only a minority require drug treatment.

• All patients should be taught the mechanisms of postural normotension volume status resistance and capacitance bed autoregulation

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.• Keep a BP log • Dietary modification (salt/fluids). • Learn physical counter maneuvers that reduce standing OH • Practice postural and resistance training.

• SYMPTOMATIC TREATMENT

Non pharmacological:

Adequate intake of salt and fluids to produce a voiding volume between 1.5 and 2.5 L of urine each 24 h is essential

Elevation of head end while sleeping.

Prolonged recumbency should be avoided when possible.

Sitting with legs dangling over the edge of the bed for several minutes before attempting to stand.

Leg-crossing with maintained contraction of leg muscles for 30 seconds compresses leg veins and increases systemic resistance.

Compressive garments, such as compression stockings and abdominal binders, are helpful occasionally but are uncomfortable.

Anemia should be corrected with erythropoietin, administered subcutaneously at doses of 25–75 U/kg three times per week. The hematocrit increases after 2–6 weeks.

A weekly maintenance dose is usually necessary. The increased intravascular volume that accompanies the rise

in hematocrit can exacerbate supine hypertension.

Pharmacological treatment

Midodrine directly acting α 1 -agonist does not cross the blood-brain barrierduration of action 2–4 h. The usual dose is 5–10 mg orally tidSide effects include pruritus, uncomfortable piloerection, and

supine hypertension especially at higher doses.

Pyridostigmine

a parasympathomimetic and a reversible cholinesterase inhibitor

enhances ganglionic transmission.

improves OH without aggravating supine hypertension

Fludrocortisone

enhances renal sodium conservation and increases the sensitivity of arterioles to NE.

At doses between 0.1 mg/d and 0.3 mg bid orally, it reduces OH, but it aggravates supine hypertension.

Susceptible patients may develop fluid overload, congestive heart failure, supine hypertension, or hypokalemia.

Specific Syndromes

• Progressive Autonomic Failure

• Idiopathic orthostatic hypotension, or progressive autonomic failure (PAF), is a primary degenerative disorder of the central and peripheral autonomic nervous systems.

• The condition may be uncomplicated by other neurological manifestations (PAF), or may be associated with• Parkinsonian features (PAF-P)• or multiple-system atrophy (PAF-MSA)

• In PAF there is a loss of cells in the ILC, loss of small myelinated fibers in the ventral roots, and loss of neurons in the dorsal vagal nuclei.

• Degeneration of sympathetic ganglia and the appearance of Lewy bodies with hyaline structures in the sympathetic ganglion cells.

• Clinical features includepostural hypotension (most important)impairment of the sweating mechanism,disturbances of heart rate and blood pressure control.

• Management is mostly non pharmacological. Drugs are used for severe symptoms

Parkinson’s Disease

• Autonomic disturbances are common in advanced disease.• Difficult to distinguish from PAF-P• Management is symptomatic and that of underlying disease

Spinal Cord Lesions

• Spinal cord lesions from any cause may result in focal autonomic deficits or autonomic hyper reflexia

• Autonomic dysreflexia describes a dramatic increase in blood pressure in patients with traumatic spinal cord lesions above the C6 level, often in response to stimulation of the bladder, skin, or muscles.

• Potential complications include intracranial vasospasm or hemorrhage, cardiac arrhythmia, and death.

• Awareness of the syndrome and monitoring of blood pressure during procedures in patients with acute or chronic spinal cord injury is essential.

Autoimmune Autonomic Neuropathy(AAN)

• Presents with the subacute development of autonomic disturbances with

OHenteric neuropathy (gastroparesis, ileus,

constipation/diarrhea), andcholinergic failure(loss of sweating, sicca complex, and a tonic

pupil)

• Autoantibodies against the ganglionic ACh receptor (A3 AChR) are present and are now considered to be diagnostic.

• Beneficial response to plasmapheresis or intravenous immune globulin has been documented

• Symptomatic management of OH, gastroparesis, and sicca symptoms is essential.

Postural Orthostatic Tachycardia Syndrome(POTS)

• Characterized by symptomatic orthostatic intolerance (not OH) and 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.

• Syncopal symptoms (lightheadedness, weakness, blurred vision) combined with symptoms of autonomic overactivity (palpitations, tremulousness, nausea) are common.

• Expansion of fluid volume and postural training are initial approaches to treatment.

• If these approaches are inadequate, then midodrine, fludrocortisone, phenobarbital, beta blockers, or clonidine may be used.

Inherited Disorders

• There are five known hereditary sensory and autonomic neuropathies (HSAN I–V).

• The most important ones are HSAN I and HSAN III (Riley-Day syndrome; familial dysautonomia).

• HSAN I is dominantly inherited and often presents as a distal small-fiber neuropathy (burning feet syndrome).

• The responsible gene, on chromosome 9q, is designated SPTLC1 . SPTLC is an important enzyme in the regulation of ceramide.

• HSAN III, an autosomal recessive disorder of infants and children that occurs among Ashkenazi Jews, 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 . Episodic abdominal crises and fever are common.

• The defective gene, named IKBKAP , is also located on the long arm of chromosome 9.

Acute Autonomic Syndromes

• An autonomic storm is an acute state of sustained sympathetic surge that results in variable combinations of alterations in blood pressure and heart rate, body temperature, respiration, and sweating.

• Causes of autonomic storm are brain and spinal cord injury, toxins and drugs, autonomic neuropathy, and chemodectomas (e.g., pheochromocytoma).