AUTHOR AND EDITOR INFORMATION

Section 1 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

INTRODUCTION

Section 2 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

Background

Autonomic dysfunction syndrome (ADS) is reported in cases of traumatic brain injury (TBI), hydrocephalus, brain tumors, subarachnoid hemorrhage, and intracerebral hemorrhage. ADS is rarely reported without an identified cause. ADS occurs when the findings of hypertension (HTN), fever, tachycardia, tachypnea, pupillary dilation, and extensor posturing are attributed to altered autonomic activity. Most recently, a new term has been put forth that seeks to more precisely characterize this condition—paroxysmal autonomic instability with dystonia (PAID).

PAID occurs as a result of severe brain injury (Rancho level less than or equal to IV) from multiple causes including traumatic brain injury (TBI), hydrocephalus, brain tumors, subarachnoid hemorrhage, and intracerebral hemorrhage. PAID is a syndrome attributed to altered autonomic activity. Clinical manifestations consist of a temperature of 38.5°C, hypertension, a pulse of at least 130 beats per minute, a respiratory rate of at least 140 breaths per minute, intermittent agitation, and diaphoresis, and are accompanied by dystonia (rigidity or decerebrate posturing for a duration of at least 1 cycle per d for at least 3 d).

Other issues that can occur because of autonomic dysregulation are ECG alterations, arrhythmias, increased intracranial pressure (ICP), hypohidrosis, subnormal temperature in flaccid limbs, and neurogenic lung disease. Usually episodic, PAID first appears in the intensive care setting but may persist into the rehabilitation phase for weeks to months after injury in individuals who remain in a low-response state.

Pathophysiology

The cause of ADS is dysregulation of the autonomic nervous system due to injury of one or more parts of the brain that contribute thereunto. Cortical areas that influence the activity of the hypothalamus include the orbitofrontal, anterior temporal, and insular regions. Subcortical areas that influence the hypothalamus include the amygdala (particularly the central nucleus), the periaqueductal gray, the nucleus of the tractus solitarius, the cerebellar uvula, and the cerebellar vermis. Damage to these areas releases control of vegetative functions and results in dysregulation of overall autonomic balance. The complex interaction of these regions is illustrated by the control of temperature and blood pressure.

The preoptic area of the hypothalamus contains heat-sensitive neurons. Temperature elevation is met with cooling measures: sympathetic activation of sweat glands is augmented, while sympathetic vasoconstriction is inhibited. Increased antidiuretic hormone (ADH) secretion causes water retention and greater sweating.

Cold is detected by two mechanisms. Initially, a decreased rate of firing of the preoptic heat-sensitive neurons is interpreted as cold, and activation of specific cold receptors also ensues. Sensations of cold are carried to the posterior hypothalamus by the spinothalamic tract, and the sympathetic nervous system is then stimulated to produce increases in the body temperature. This occurs through shivering, vasoconstriction, piloerection, and inhibition of sympathetically induced sweating. Integration of cold sensory input and the warm sensory input from the anterior hypothalamus occurs in the posterior hypothalamus. Pyrogens alter the set point of the hypothalamic control, and raising it promotes fever.

Isolated impairment of thermoregulation after extremely severe brain injury has been reported. In this reported case, episodic elevations in temperature during the summer months were reported. Upon controlled manipulation of the environment, failure to manage temperature elevations was documented. Even paradoxical responses to temperature decreases were noted. Other features of dysautonomia were not described in this case.

Both the anterior and the posterior hypothalamus interact with the brainstem through multiple feedback loops. The midbrain tegmentum gives rise to descending pathways that inhibit a thermogenic drive from the brainstem. Decerebrating lesions result in hyperthermia in rats. Fever in patients with brain injury is most often due to infection. Less frequently, fever is due to deep vein thrombosis (DVT) or medications, and even less frequently, fever is due to impaired autonomic regulation due to the injury. In addition, dystonia leads to a hypermetabolic state and further temperature elevations. The proposed mechanism for this occurs when lesions in the midbrain block interfere with normal inhibitory signals to the pontine and vestibular nuclei, thus making them tonically active. A facilitation signal is then transmitted to the spinal cord control circuits. This results in a hyperexcitable spinal reflex that can be evoked by sensory input signals whose thresholds are below those required for motor

excitation.

Blood pressure is controlled by the interaction of several cortical and subcortical areas of the brain: the hypothalamus, thalamus, amygdala, orbitofrontal cortex, nucleus ambiguus, and nucleus tractus solitarius. The orbitofrontal cortex is believed to promote parasympathetic activity and inhibit sympathetic activity. Dysregulation occurs when these areas are damaged and causes a cortically provoked release of adrenomedullary catecholamines during ADS episodes resulting in an increased blood pressure, tachycardia, and tachypnea. The previous cases of episodic elevations of blood pressure after TBI contrast with the more constant and persistent hypertension that frequently develops but still remains consistent with ADS. The fluctuations occurred early in the course of the episodic cases (the second day). Plasma catecholamines were noted as being elevated at the time of the blood pressure fluctuations (Blackman, 2004).

In experimentally induced brain trauma, an elevation of catecholamine and acetylcholine levels occurs. Hypotension, cardiac arrhythmias, or hypertension can result. Milder brain injuries yield acetylcholine level elevation. More severe injuries yield catecholamine level elevation in magnitudes that are proportional to the severity of injury. Coincidentally, the catecholamine levels are inversely proportional to the Glasgow Coma Scale (GCS) scores soon after TBI.

Frequency

International

Following brain injury, about 15-33% of patients acutely develop ADS. Within the population of individuals with severe TBI, dysautonomia syndrome is not more common for any particular subset of GCS scores, age, sex, or mode of injury. Neuroimaging revealed more frequent evidence of diffuse axonal injury (DAI) and brainstem injury in those who developed dysautonomia.

Mortality/Morbidity

Autonomic dysfunction is associated with increased morbidity. While the length of stay in acute services is not different from those without ADS, the length of stay in rehabilitation services is longer on the average. The risk of myocardial infarction (MI) and secondary injury due to hemorrhage or elevated intracerebral temperature is of concern. ADS is also associated with less favorable functional outcomes.

CLINICAL

Section 3 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

History

Autonomic dysfunction syndrome (ADS) usually occurs in the setting of severe traumatic brain injury (TBI) associated with diffuse axonal injury (DAI). ADS must be distinguished from other syndromes presenting similarly, and it is a diagnosis of exclusion as there are no pathognomonic tests or findings.

• The other syndromes to consider include neuroleptic malignant syndrome, serotonin syndrome, malignant hyperthermia, and thyroid storm.
• • The use of neuroleptics generally is contraindicated in patients with brain injuries, so classic neuroleptic malignant syndrome is unlikely to be encountered in these patients. However, withdrawal of premorbidly used dopaminergic agents or the use of metoclopramide can precipitate neuroleptic malignant syndrome, so this condition must be considered.
  • The use of serotonergic agents is common in those with brain injury; consideration of serotonin syndrome is therefore essential.
  • Malignant hyperthermia mainly occurs after surgery during which there was exposure to anesthetic agents, particularly succinylcholine. Malignant hyperthermia in the rehabilitation setting most often is seen in patients with spinal cord injury because of their increased susceptibility.
  • Thyroid storm is a potential complication of trauma to the neck with release of excess thyroid hormone from the injured thyroid gland.

Physical

Patients with ADS present with a combination of typical physical findings. The elevation of temperature may vary in severity from low-grade to high fevers. Fever frequently and justifiably prompts a detailed search for infectious etiologies. The individual's temperature may vary from being elevated to being within the reference range, or it may stay elevated. One important aspect of elevated temperature in those with TBI is that intracerebral temperature may significantly exceed measured body temperature due to impaired blood flow in the injured area. Thus, temperature control should be prompt and aggressive in those with TBI. Cephalosporins, ibuprofen, and H2 blockers help reduce the fever and/or help treat the cause of fever; therefore, they frequently are used in patients with TBI.

• Findings of ADS may be prominent during the intensive care stages of the case. Findings include the following:
• • Hypertension
  • Fever
  • Tachycardia
  • Tachypnea
  • Pupillary dilation
  • Extensor posturing
  • Diaphoresis
• The combination of all findings does not always occur. Often tachycardia, fever, and hypertension are the main presenting signs.
• Because the syndrome includes features in common with acute infection, ruling out infection is paramount.

Causes

The cause of ADS is dysregulation of the autonomic nervous system due to injury of one or more parts of the brain that contribute thereunto. See Pathophysiology.

DIFFERENTIALS

Section 4 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

Other Problems to be Considered

Sepsis
Meningitis
Neuroleptic malignant syndrome
Lethal catatonia
Malignant hyperthermia
Infection
Thyroid storm
Delirium tremens
Serotonin syndrome

WORKUP

Section 5 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

Lab Studies

• CBC - To reveal potential infection (Elevated white blood cell and/or platelet counts may signal infection.)
• Blood cultures - To rule out sepsis
• Sputum cultures - To rule out pneumonia
• Urine cultures and urinalysis - To rule out urinary tract infection
• Sputum Gram stain - To rule out infection
• Plasma catecholamine levels - May be of interest acutely but are not required for the diagnosis
• Thyroid panel - To rule out thyroid storm
• Random chemistry panel – To rule out neuroleptic malignant syndrome
• Plasma creatine kinase and troponin levels - To rule out acute MI, neuroleptic malignant syndrome, and serotonin syndrome

Imaging Studies

• Chest radiograph - To rule out pneumonia and atelectasis
• Duplex ultrasound - To rule out DVT
• ECG - To rule out MI
• Head CT scan or MRI - To rule out abscess, encephalitis, or hydrocephalus

Procedures

• Lumbar puncture - To rule out meningitis

TREATMENT

Section 6 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

Rehabilitation Program

Physical Therapy

Severe episodes of autonomic dysfunction syndrome (ADS) may preclude or delay any of the components of a contemporary multidisciplinary rehabilitation program. Physical therapy may have to be held episodically because labile blood pressure, ICP, heart rate, and temperature may preclude participation. Of course, it is preferable to continue not only with passive range of motion (PROM) but with as much of the functional program as possible; monitor these symptoms during therapy.

Occupational Therapy

Continue occupational therapy as regularly as possible, with the same considerations as for physical therapy.

Speech Therapy

Patients with ADS usually have severe impairment of alertness. Thus, speech therapy may not yet be appropriate.

Medical Issues/Complications

Severe muscle rigidity can result is muscle rupture or in rhabdomyolysis. Fever is viewed as a source of secondary injury in individuals with traumatic brain injury (TBI) because marginal cerebral blood flow fails to provide for normal brain cooling. This may result in a brain temperature that is higher than the measured core temperature. The resulting increase in metabolic demand may not be met by increasing blood flow, so local areas of hypoxia and further neuronal dysfunction and death ensue.

HTN and tachycardia could theoretically increase the risk of developing hemorrhage from injured blood vessels. Conversely, they are also used as part of the treatment for vasospasm, which frequently occurs in cases of subarachnoid hemorrhage.

Prolonged severe diaphoresis may result in dehydration and electrolyte abnormalities.

Surgical Intervention

Surgery is not part of the treatment for ADS.

Consultations

Consultation from infectious disease experts is appropriate though not always necessary in this context.

MEDICATION

Section 7 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

Because a wide array of neurotransmitters are involved in the pathways of autonomic control, a wide array of medications exert an influence on this system.

The effectiveness of both chlorpromazine and bromocriptine (dopamine antagonist and dopamine agonist, respectively) in the treatment of autonomic dysfunction syndrome (ADS) illustrates the complexity of the neurotransmitter regulation pathways and the variability of the lesions that can cause the syndrome.

Propranolol, a lipophilic beta-blocker, has successfully been used to control ADS. Beta-blockade has been shown to decrease the HTN and hemodynamic abnormalities. Beta-blockade does not alter diaphoresis, which is mediated via sympathetic cholinergic neurons. As with all beta-blockers, use caution when using in those with diabetes and asthma.

Clonidine has been effective in normalizing plasma epinephrine and in reducing plasma norepinephrine levels, which effectively decreases blood pressure. Alpha-adrenergic and beta-adrenergic blockers prevent ECG changes and cardiac arrhythmias associated with traumatic brain injury (TBI). However, clonidine is known to cause sedation.

Bromocriptine has been used and has helped with the hyperthermia and diaphoresis that occurs with ADS.

Dantrolene has been used with good results on extensor posturing but minimal effects on other components of ADS.

Morphine has been effective in abolishing ADS, as has naltrexone.

Drug Category: Beta-blockers

May block effect of vasodilators, decreasing platelet adhesiveness and aggregation, stabilizing the membrane, and increasing the release of oxygen to tissues.

Drug Category: Dopamine agonists

Inhibit noxious input to spinal cord.

Drug Name	Chlorpromazine (Thorazine)
Description	Mechanisms include blocking postsynaptic mesolimbic dopamine receptors, anticholinergic effects, and depression of RAS. Blocks alpha-adrenergic receptors and depresses release of hypophyseal and hypothalamic hormones. However, as a rule, dopamine antagonists are avoided in patients with TBI
Adult Dose	25-50 mg PO q4-6h 25-50 mg IM q6-8h if symptoms persist for 2-3 d
Pediatric Dose	Not established
Contraindications	Documented hypersensitivity; bone marrow suppression, narrow-angle glaucoma, severe liver disease, or cardiac disease
Interactions	Other CNS depressants, anticholinergics, or anticonvulsants; antihypertensives may cause additive effect; coadministration with epinephrine may cause hypotension
Pregnancy	C - Safety for use during pregnancy has not been established.
Precautions	May cause pseudoparkinsonism; akathisia is a common extrapyramidal reaction in elderly patients; lowers seizure threshold and increases risk of seizures in patients with history of seizures

Drug Category: Muscle relaxants

Modulate muscle contractions.

Drug Category: Opioids

Pain control is essential to quality patient care. Analgesics such as opioids ensure patient comfort, promote pulmonary toilet, and have sedating properties, which are beneficial for patients who have sustained trauma or injuries.

Drug Name	Naltrexone (ReVia)
Description	Cyclopropyl derivative of oxymorphone that acts as a competitive antagonist at opioid receptors. ADS has been found to be responsive to naltrexone.
Adult Dose	25 mg PO initially; if no withdrawal signs within 1 h, administer another 25 mg Maintenance dose: 50-150 mg PO 3 times/wk
Pediatric Dose	Not established
Contraindications	Documented hypersensitivity; acute hepatitis or liver failure
Interactions	Inhibits effects of opiates
Pregnancy	C - Safety for use during pregnancy has not been established.
Precautions	Caution in hepatic impairment

FOLLOW-UP

Section 8 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

Further Inpatient Care

• The length of stay in rehabilitation is usually reported as being longer for those patients who experience autonomic dysfunction syndrome (ADS). Other than this observation, no specific alterations from a typical multidisciplinary acute inpatient rehabilitation program are expected in this population.
• If actual myocardial damage is identified as a result of the syndrome, observe appropriate cardiac rehabilitation principles during the head injury rehabilitation program.

Further Outpatient Care

• The outpatient setting is rarely the context for ADS to present.
• The usual outpatient therapy programs and concern regarding family functioning and community reintegration issues pertain to outpatient care.
• Rarely, continued medication use is required long term. Thus, monitoring for common side effects and minimizing medications that impair cognition are required.

Transfer

• Transfer to either the neurosurgery service or an ICU setting is rarely necessary for patients with ADS, although it is conceivable in the event of dangerously high blood pressure and tachycardia.

Complications

• Increased sensitivity of neurons to elevated temperature occurs during the acute phase of TBI. In animals, functional differences are discernible between those with temperatures in excess of 38°C and those whose temperature is maintained below 38°C. In one study, 73% of patients with dysautonomia had temperatures above 38°C for 2 weeks after injury, contrasted with only 18% of those without dysautonomia.
• Posturing increases energy expenditure by 150-250%. These features increase the risk that those with dysautonomia will sustain secondary injury to the brain.

Prognosis

• While those who had dysautonomia did make functional gains, their outcomes as measured by scores of the Glasgow Outcome Scale (GOS) and the Functional Independence Measure (FIM) were poorer than those of patients without dysautonomia. They also had more difficulty with memory and longer periods of posttraumatic amnesia (PTA) than those without dysautonomia. Duration of ICU stay was the same as controls, but length of rehabilitation stay was greater for those with dysautonomia. On the average, the duration of the dysautonomia (as measured by cessation of sweating) was about 75 days.

Patient Education

• Explaining ADS to the patient is rarely an issue, as patients are usually cognitively compromised at the time of manifestation of the syndrome. However, reducing the fear of family members is important. Family should understand that this syndrome is seen in those with brain injury, that it is almost always controllable with medications, and that it does not usually remain a long-term problem.

MISCELLANEOUS

Section 9 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

Medical/Legal Pitfalls

• Failure to recognize and appropriately treat autonomic dysfunction syndrome (ADS)
• Failure to diagnose and treat a significant infection
• Failure to recognize and treat one of the other more life-threatening differentials mentioned above (See Differentials.)

Special Concerns

• There are other forms of hypothalamic instability noted in patients with TBI. Manifestations such as neuroleptic malignant syndrome, lethal catatonia, and malignant hyperthermia are described below.
• • Neuroleptic malignant syndrome is an idiosyncratic reaction to neuroleptics and other psychotropic medications. This syndrome is normally seen after use of potent drugs such as haloperidol, thiothixine, or piperazines, and it is thought to be due to alterations of central neuroregulatory mechanisms. Metoclopramide, another dopamine-altering medication, has also been associated with the syndrome. Blockade, depletion of dopamine, or withdrawal of dopaminergic medications is believed to be causal. The clinical picture is hyperpyrexia, hypertonicity, altered levels of consciousness, and autonomic dysfunction. Abnormal electrolytes, elevated WBC counts, elevated liver function tests, and elevated CK are common laboratory findings. Bromocriptine and dantrolene are the recommended treatment.
  • A similar disorder, more frequently described before the advent of neuroleptic medications, is lethal catatonia. The relationship between lethal catatonia and neuroleptic malignant syndrome is the subject of speculation. Clinically, lethal catatonia is a syndrome that develops slowly (over 2 wk) and is characterized by intense motor excitement day and night, violence, insomnia, anorexia, intermittent posturing, rigidity, and psychiatric disturbances. Tachycardia, diaphoresis, dehydration, labile or high blood pressure, and high fever also may occur. Exhaustion eventually supervenes, with continued fever and either rigidity or flaccidity, followed by demise due to cardiovascular collapse. Electroconvulsive therapy has recently been found to be helpful.
  • A third syndrome, malignant hyperthermia, is not viewed as hypothalamic in nature. Rather, it is due to hypermetabolism in muscle triggered by medication exposure, typically anesthetic agents. Hyperpyrexia; tachycardia; muscle rigidity; and elevated potassium, calcium, magnesium, and CK are typical signs. Treatment consists of discontinuing the causal drug, use of dantrolene, and supportive care. Stress-induced malignant hyperthermia, without exposure to the usual offending medications, has been reported.

REFERENCES

Section 10 of 10

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

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Article Last Updated: Oct 4, 2006