The autonomic nervous system syndrome may also be classified anatomically into telencephalic, diencephalic, brain stem, and spinal cord disorders ( ...Ia.b]e.,..21-5 ).
Telencephalon Syndromes. Temporolimbic seizures may induce changes in heart rate, heart rhythm, and blood pressure. Cardiovascular manifestations of seizures include sinus tachycardia or bradyarrhythmias (including sinus arrest) with syncope. Seizure-induced ventricular tachycardia and fibrillation have been implicated in sudden death. Other autonomic manifestations of seizures include flushing, pallor, shivering, sweating, symmetrical or unilateral piloerection, visceral sensations, vomiting (ictus emeticus), and respiratory changes.^ , y Ischemic damage to the insula
TABLE 21-5 -- LEVEL-SPECIFIC CENTRAL AUTONOMIC NERVOUS SYSTEM DISORDERS
Episodic hyperhidrosis with hypothermia
Paroxysmal autonomic hyperactivity
Fatal familial insomnia
Neuroleptic malignant syndrome Serotonin syndrome Tumors
Vertebrobasilar disease Synngobulhia
Arnold-Chian type I malformation
Inflammation (multiple sclerosis, poliomyelitis)
has been associated with cardiac arrhythmias and contralateral hyperhidrosis. When the cingulate and paracentral cortices are involved, urinary incontinence may occur because of uninhibited bladder contractions.
Diencephalon Syndromes. Disorders affecting the hypothalamus may produce disturbances of thermoregulation, osmotic balance, endocrine function, and state of alertness.^ Chronic expanding lesions such as tumors or granulomas cause hypothermia, whereas acute lesions may cause hypothermia or hyperthermia. Wernicke's encephalopathy should be suspected in alcoholic and other malnourished patients presenting with unexplained hypothermia, particularly in the presence of disturbances of consciousness and oculomotor function. Episodic hyperhidrosis with hypothermia may occur with no apparent cause, y as a manifestation of agenesis of the corpus callosum,y or during paroxysms of autonomic hyperactivity.
Although such paroxysmal autonomic hyperactivity in patients with brain tumors and other diseases of the diencephalon has been referred to as diencephalic seizures, this term is a misnomer. The EeG shows no ictal activity, and the episodes are refractory to antiepileptic drugs. Paroxysmal autonomic hyperactivity was first described in patients with tumors situated in the region of the third ventricle that caused hydrocephalus and abrupt increases in intracranial pressure. The majority of cases, however, are due to severe closed head injuries marked by episodic increases in intracranial pressure and acute hydrocephalus following sub-arachnoid hemorrhage.^
Sympathetic hyperactivity also occurs in a transmissible spongiform encephalopathy characterized by severe atrophy of the anteroventral and dorsomedial nuclei of the thalamus. This autosomal dominant disorder presents with disruption of endocrine circadian rhythms, motor dysfunction, and progressive intractable insomnia--thus its name, familial fatal insomnia (see Chapter.43 )[i6'
Brain Stem Syndromes. Cerebrovascular disease is the most common cause of dysautonomia associated with brain stem dysfunction. Transient ischemic attacks in the basilar artery territory may present with paroxysmal hypertension before any focal neurological deficit becomes apparent. Lateral medullary infarction (Wallenberg's syndrome) produces Horner's syndrome and, occasionally, more severe autonomic abnormalities such as profound bradycardia, supine hypotension, or central hypoventilation.^
Other brain stem disorders associated with autonomic dysfunction include tumors, syringobulbia, Arnold-Chiari malformation type 1, multiple sclerosis, and poliomyelitis. Brain stem tumors may present with intractable vomiting, orthostatic hypotension, or paroxysmal hypertension. Syringobulbia may produce Horner's syndrome, orthostatic hypotension, cardiovagal dysfunction, lability of arterial pressure, and central hypoventilation. y Syncope, sleep apnea, and cardiorespiratory arrest have been reported in association with the Arnold-Chiari malformation type 1. Less common manifestation of brain stem dysfunction include hypertension due to involvement of the medullary reticular formation in poliomyelitis (see Chapter^.!); autonomic hyperactivity, most likely due to disinhibition of preganglionic sympathetic and parasympathetic neurons in tetanus (see Chapter s! ); and fulminant neurogenic pulmonary edema due to demyelination of the area surrounding the NTS in patients with multiple sclerosis (see Chapter48 ).
Spinal Cord Syndrome. Traumatic spinal cord injury, particularly injury above the T5 level, is associated with severe and disabling cardiovascular, gastrointestinal, bladder, and sexual dysfunction. These patients have both supine and orthostatic hypotension and are at risk of developing bradycardia and cardiac arrest during tracheal suction or other maneuvers that activate the vagovagal reflexes. Vasopressin and the renin-angiotensin-aldosterone system have an enhanced role in maintenance of orthostatic arterial pressure in patients with spinal cord lesions. Lack of vasomotor and sudomotor thermoregulatory responses below the level of the lesion may lead to severe hypothermia or hyperthermia in response to changes in environmental temperature. Acute spinal injury or spinal shock produces a paralytic atonic bladder. The pattern of dysfunction seen in the chronic stages of disease, however, depends on the level of the lesion. Lesions above the sacral parasympathetic nucleus produce spastic bladder, commonly with detrusor-sphincter dyssynergia, whereas lesions of the conus medullaris produce a flaccid, areflexic bladder.
In patients with chronic tetraplegia with lesions at or above the T5 level, stimulation of the skin, muscle, or viscera innervated by segments below the lesion may result in a massive reflex activation of sympathetic and sacral parasympathetic outflows, referred to as autonomic dysreflexia. y Stimuli that trigger autonomic dysreflexia arise primarily from the bladder, bowel, or skin. Vasodilation above the level of the lesion produces flushing of the face, chest, and upper arms and congestion of the nasopharyngeal mucosa. There may be excessive sweating above the anesthetic dermatome, piloerection, pallor in the abdomen and lower extremities, and pupillary dilatation. Severe hypertension is a prominent feature of autonomic dysreflexia and can result in hypertensive encephalopathy or intracranial, subarachnoid, or retinal hemorrhage. The combined parasympathetic and sympathetic stimulation may cause potentially dangerous supraventricular and ventricular arrhythmias.
Multiple sclerosis (MS) may affect autonomic pathways at the level of the spinal cord, brain stem, or diencephalon. Bladder, bowel, and sexual dysfunction are prominent autonomic manifestations of MS. The pathophysiological basis of the bladder dysfunction seen in patients with MS is detrusor hyperreflexia and detrusor-sphincter dyssynergy. Subclinical abnormalities in cardiovascular sympathetic and parasympathetic function and abnormal thermoregulatory sweating detected by testing in the autonomic laboratory are common in patients with MS.
Syringomyelia produces partial interruption of sympathetic output pathways in the intermediolateral cell columns. Its autonomic manifestations include Horner's syndrome, sudomotor and vasomotor dysfunction, and trophic changes in the limbs, especially the hands.
Tetanus and the stiff-person syndrome may be associated with sympathetic hyperactivity due to lack of synaptic inhibition of preganglionic autonomic neurons. This results in hyperpyrexia, sweating, tachycardia, hypertension, tachypnea, and pupillary dilatation, usually associated with the muscle spasms.
_TABLE 21-6 -- TOPOGRAPHIC OR ORGAN RESTRICTED AUTONOMIC DISORDERS
Disorders of the Pupil Affecting parasympathetic outflow Third nerve lesion Argyll Robertson pupil Adie's pupil
Affecting sympathetic outfiow Horner's syndrome Pourfour du Petit syndrome Facial Hyperhidrosis and Flushing Gustatory sweating Harlequin syndrome Cluster headache
Vasomotor and Sudomotor Disorders of the Limb
Complex neuropathic pain syndromes
Painful distal peripheral neuropathy
Nerve trauma (causalgia)
Undetermined and multifactorial: Complex regional pain syndrome Refex sympathetic dystrophy Neurogenic Bladder
Spastic bladder with or without detrusor-sphincter dyssynergia
Topographic or Organ-Specific Disorders ( T.a.b.l.e..?.!,^. ) PUPILS
Argyll Robertson Pupils. Argyll Robertson pupils are irregular and smaller than normal in darkness and demonstrate lack of the pupillary light reflex with preserved pupillary constriction during accommodation and convergence for near objects. These features, as in patients with large pupils with light-near dissociation, usually indicate a lesion in the rostral midbrain at the level of the posterior commissure.
Adie's Pupil. These tonic pupils are large and irregular in shape, poorly reactive to light, and indicate a lesion of the ciliary ganglion or short ciliary nerves. On slit-lamp evaluation, regional palsies of the iris sphincter are visible. These pupils have a hypersensitive constrictor response to administration of diluted muscarinic agonists, such as a 2.5 percent solution of methylcholine chloride or a 0.1 percent solution of pilocarpine. Adie's pupils are tonic pupils associated with reduced or absent tendon reflexes.
Horner's Syndrome. A unilateral small pupil is commonly due to underactivity of the ipsilateral sympathetic pathways. Miosis is commonly associated with ptosis (lid droop) due to sympathetic denervation of the tarsal muscle and facial anhidrosis (loss of sweating). This combination is known as Horner's syndrome. Oculosympathetic paralysis occurs ipsilaterally owing to (1) central lesions involving the hypothalamospinal pathways at the dorsolateral brain stem tegmentum (e.g., a lateral medullary infarct); (2) preganglionic lesions (e.g., compression of the sympathetic chain by a tumor in the apex of the lung); or (3) postganglionic lesions at the level of the internal carotid plexus (e.g., lesions of the cavernous sinus). Postganglionic Horner's syndrome does not result in facial anhidrosis because pupilodilator and sudomotor axons follow separate paths along branches of the internal and external carotid arteries, respectively.
Local instillation of drugs that affect sympathetic neurotransmission in the pupil helps to localize the lesion causing oculosympathetic paralysis. Cocaine hydrochloride (5 to 10 percent), which prevents NE reuptake, will not dilate a pupil that is miotic because of a lesion anywhere in the sympathetic pathway. The responsible lesion can be further localized by hydroxyamphetamine hydrobromide (Paredrine 1 percent), which is an indirect sympathomimetic agent that releases norepinephrine from the synaptic terminals, thus eliciting pupillary dilatation in patients with preganglionic but not postganglionic Horner's syndrome. Phenylephrine hydrochloride (Neo-Synephrine) is a direct alpha agonist that in a low concentration (1 percent) dilates the pupil only in patients with a postganglionic Horner's syndrome associated with denervation hypersensitivity of the pupil.
Facial flushing may result from the release of tonic sympathetic vasoconstriction, active sympathetic vasodilatation, increased parasympathetic activity via the greater petrosal nerve, and the release of vasoactive peptides. Gustatory sweating and flushing occur in the following conditions: idiopathic hemifacial hyperhidrosis associated with hypertrophy of the sweat glands; following bilateral cervicothoracic sympathectomy with reinnervation of the superior sympathetic ganglion by preganglionic sympathetic fibers destined for the sweat glands; after local damage to the autonomic fibers traveling with the peripheral branches of the trigeminal nerve (e.g., in parotid or submaxillary gland surgery or V3 zoster) with reinnervation of sweat glands and blood vessels by parasympathetic vasodilator fibers destined for the salivary glands; and accompanying peripheral neuropathies, most frequently diabetes mellitus. U
Sympathetic failure may produce loss of sweating and flushing as manifestations of Horner's syndrome. In contrast, the Porfour du Petit syndrome consists of a dilated pupil with flushing and hyperhidrosis due to sympathetic hyperactivity. This syndrome is seen in patients with sympathetic nervous system lesions, frequently following injuries of the neck that damage the sympathetic plexus around the carotid artery. The harlequin syndrome consists of a sudden onset of flushing and sweating on one side of the face. This disorder may be due to lesions in the contralateral central or peripheral sympathetic nervous system pathways. Attacks of cluster headache may be accompanied by ipsilateral signs of parasympathetic hyperactivity (lacrimation and nasal discharge), sympathetic overactivity (forehead sweating), and ocular sympathetic paralysis (miosis and ptosis). The mechanisms producing these phenomena have no widely accepted explanation. Changes in both the
Hyperhidrosis may be generalized or localized. Localized hyperhidrosis is rare and may occur with injury to the spinal cord (e.g., in syringomyelia), peripheral nerves (e.g., with partial median or sciatic nerve injury), or eccrine sweat glands. Perilesional hyperhidrosis may surround an anhidrotic region produced by a lesion of the sympathetic ganglia or rami. The axillary eccrine sweat glands are activated by thermal stimuli, whereas the palmar and plantar glands are activated by emotional stimuli. Primary or essential hyperhidrosis affects the axillary, palmar, and plantar regions and may be familial. Generalized hyperhidrosis may be secondary to infections, malignancies, or neuroendocrine disorders (e.g., pheochromocytoma, thyrotoxicosis, acromegaly, carcinoid, anxiety, hypotension, hypoglycemia, and cholinergic agents).y
Vasomotor disorders in the limbs include Raynaud's phenomenon, acrocyanosis, livedo reticularis, vasomotor paralysis, and erythromelalgia. Raynaud's phenomenon is the episodic, bilateral, symmetrical change in skin color (pallor, followed by cyanosis and terminating in rubor after rewarming) that is provoked by cold or emotional stimuli. This response is due to episodic closure of the digital arteries. There is, however, no consistent evidence of exaggerated sympathetic outflow to the skin. Raynaud's phenomenon may be associated with connective tissue disease (e.g., scleroderma, rheumatoid arthritis, psoriasis), occupational trauma (such as the use of pneumatic hammers, chain saws producing vibration), the thoracic outlet syndrome, the carpal tunnel syndrome, or certain drugs (e.g., beta blockers, ergot alkaloids, methysergide, vinblastine, bleomycin, amphetamines, bromocriptine, and cyclosporine). y
Acrocyanosis is a symmetrical distal blue discoloration, usually occurring below the wrists and ankles, that is due to arteriolar constriction and is aggravated by cold. In contrast, livedo reticularis is a vasomotor disorder that affects the extremities and the trunk and is due to vasospasm with obstruction of the perpendicular arterioles or stasis of blood in the superficial veins. It may be a benign disorder or may be associated with vasculitis, antiphospholipid antibodies (Sneddon's syndrome), connective tissue disease, hyperviscosity syndrome, thrombocythemia, and drugs (e.g., amantadine, quinine, and quinidine). y
Vasomotor paralysis may be seen in patients with lesions of the sympathetic pathways at the level of the spinal cord, preganglionic nerves, ganglia, or postganglionic nerves. Examples include surgical sympathectomy (e.g., for treatment of selective cases of hyperhidrosis, Raynaud's phenomenon, and reflex sympathetic dystrophy), trauma (e.g., carpal tunnel syndrome, ulnar nerve lesions), and tumor infiltration (e.g., Pancoast's tumor, malignant retroperitoneal disease).
Erythromelalgia is a painful acral erythematous condition that occurs with cutaneous warming and is associated with an intense burning sensation. It may occur in patients with small-fiber neuropathies. The mechanism may be activation of neurogenic flare by a polymodal C nociceptor axon and release of vasodilator and algogenic neuropeptides such as substance P. y
Reflex sympathetic dystrophy is a pain syndrome defined as a continuous burning pain, hyperpathia (exaggerated response to painful stimuli), and allodynia (perception of an innocuous stimulus as painful) in a portion of an extremity. This disorder is associated with signs of sympathetic hypoactivity or hyperactivity and usually follows minor trauma that does not involve major nerves. Causalgia is a similar syndrome that occurs after partial injury of a nerve or one of its major branches. Vasomotor and sudomotor instability, manifestations of sympathetic hyperactivity or hypoactivity, are commonly seen. Reflex sympathetic dystrophy is not a single pathological entity, but different central, peripheral, and psychogenic mechanisms may coexist in a particular case. Sympathetic blockade may be of benefit. y
Disturbances at different levels of the bladder control system result in the development of neurogenic bladder. Neurogenic bladders can be subdivided into two types: the reflex or upper motor neuron type, and the nonreflex or lower motor neuron type. The terms reflex and nonreflex denote the presence or absence, respectively, of bulbocavernosus and anal reflexes. The reflex type of neurogenic bladder includes the uninhibited bladder associated with lesions of the medial frontal region that results in urinary incontinence but not urinary retention because the detrusor-sphincter synergy is preserved. The automatic bladder results from lesions of the spinal cord that interrupt the pathway from the pontine micturition centers. An automatic bladder is associated with urgency, frequency, incontinence, and urinary retention that is due to detrusor-sphincter dyssynergia. The lower motor neuron type of neurogenic bladder, such as that occurring with lesions of the cauda equina or peripheral nerves, is characterized by incomplete bladder emptying, urinary retention, and overflow incontinence. y
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