Cerebrally mediated autonomic dysfunction (CMAD) is a syndrome of paroxysmal autonomic nervous system hyperactivity (increased heart rate, respiratory rate, blood pressure, temperature, and sweating) and dystonia resulting from a brain lesion. It is also referred to as paroxysmal dysautonomia, autonomic storm, paroxysmal sympathetic hyperactivity, or mesencephalic seizure.
Any brain lesion, from trauma, infection, hemorrhage, infarction, brain tumor, cerebral hypoxia, or degeneration can cause this dysfunction. It is a different entity from the autonomic dysreflexia that develops in spinal cord injury.
Epidemiology including risk factors and primary prevention
The incidence of CMAD in adults with traumatic brain injury (TBI) is reported as 8-33%.3-5 It usually develops in early recovery phase following brain injury. Patients with severe injury (low Glasgow coma scores, longer coma duration), diffuse axonal injury (DAI), and brainstem lesions are at high risks5.
The pathophysiology of CMAD is largely unknown. There are two hypotheses. One is that disconnection between the cortex and the diencephalon and upper brainstem results in loss of central inhibitory regulation of control centers in the medulla responsible for vital signs6. Another hypothesis involves abnormal afferent stimulus processing due to imbalance between excitation and inhibition. Afferent stimulations (pain, loud noises, discomfort, etc.) are conveyed to the central nervous system producing efferent outputs manifesting as autonomic dysfunction. Hyperreflexic response to the peripheral afferent stimulation perpetuates autonomic dysfunction7.
Disease progression including natural history, disease phases or stages, disease trajectory (clinical features and presentation over time)
- New onset/acute
CMAD usually develops in the acute phase following brain injury8. Noxious stimuli precipitates paroxysmal changes in autonomic activity, which can manifest as hypertension, tachycardia, hyperthermia, tachypnea, and diaphoresis, although episodes may be unprovoked. Individual episodes vary in intensity and duration but rarely persist for more than several hours. The clinical features may be stereotypical, although can vary between episodes. An extremely hypermetabolic phase occurs during the episode.
The frequency of episodes is highly variable. The risk of developing joint contractures is high during this period.
These episodes are generally self-limited. Over a period of weeks, episodes typically become less pronounced in frequency, duration, and intensity. Dystonia may persist even after vital signs have stabilized and diaphoresis resolves.
Autonomic dysfunction may rarely be associated with life-threatening cardiac arrhythmias or myocardial infarction.
Specific secondary or associated conditions and complications
Resting energy expenditure during episodes of CMAD is as high as three times of norm, therefore adequate nutrition is important to prevent severe weight loss9. Patients with CMAD required a longer hospital stay and had higher hospital cost; they developed a higher rate of complications, and made less neurological recovery in acute care after brain injury10,11.
2. ESSENTIALS OF ASSESSMENT
Medical conditions that could precipitate sympathetic over activity such as infection, pain, medications, electrolyte imbalance or constipation should be ruled out. Malignant neuroleptic syndrome and serotonin syndrome should be differentiated. Haloperidol, chlorpromazine, metoclopramide, lithium, and abrupt weaning of levodopa can cause malignant neuroleptic syndrome. Inadequate withdrawal of narcotics or sedatives can cause delirium. Persistent high blood pressure, respiratory rate, heart rate, and temperature without paroxysmal episodes are unlikely to be central dysautonomia.
- Low level of cognitive function (Rancho Los Amigos score 2-3)
- Paroxysmal increase in heart rate, respiratory rate, blood pressure and temperature
- Dilated pupils
- Dystonia — decorticate or decerebrate rigidity, bruxism, opisthotonus
- Normal resting vital signs between episodes
- Frequent, stereotyped, generalized startling responses
Clinical functional assessment
The patients are typically dependent in all activities of daily living (ADLs), and are sometimes in a vegetative or minimally conscious state.
Complete blood cell count helps to rule out acute infection, along with blood, urine, or sputum cultures as indicated. High blood creatine kinase (CK) can be seen in severe dystonia but is not diagnostic. However, severity of CMAD is not directly correlated with plasma level of epinephrine and norepinephrine12.
Imaging is not diagnostic for CMAD, but there is a high incidence of diffuse lesions, especially associated with the lesions in the dorsolateral aspect of the midbrain, upper pons and deep gray matter nuclei. However, no specific focal injury lesion is related with CMAD; diffuse large lesions are at higher risk. Computed tomography of the head helps rule out progressive posttraumatic hydrocephalus.
Supplemental assessment tools
Evaluation to rule out other causes of paroxysmal symptoms (e.g. epilepsy, thyroid storm, medication withdrawal) is indicated based on clinical considerations.
Early predictions of outcomes
The shorter the duration of episodes, the better the outcome. Empirically, patients who respond well to initial trial of medication trial tend to have a better outcome.
Decreasing noxious stimulation and keeping the environment calm and noise-free is helpful in reducing precipitating factors.
Social role and social support system
Informed family members can help by reducing overstimulation.
No standard evidence-based prevention or treatment has been established. All treatment options are individual and anecdotal.
3. REHABILITATION MANAGEMENT AND TREATMENTS
Available or current treatment guidelines
The first step is avoidance of overstimulation and reduction of noxious stimuli. The second step is trial of medications. All treatment trials are empirical and may require frequent adjustments based on trial and error. Most commonly opiate agonists (morphine, methadone, fentanyl), dopamine agonists (bromocriptine, carbidopa) and antagonist (chlorpromazine), beta-blockers (propranolol, labetolol, metoprolol, atenolol), alpha2-agnost (clonidine), GABA agonists (clonazepam, midazolam, diazepam), gabapentin and intrathecal baclofen are used, but the effects are inconsistent13. Anti-epileptic drugs (phenobarbital, phenytoin, and carbamazepine) were reportedly ineffective13,14.
At different disease stages
- Potential curative interventions
Identify and address precipitating causes. If possible, replace medications that can cause malignant neuroleptic-like syndrome (e.g., metochlopramide). Correct electrolyte imbalance. Remove or reduce noxious stimulation.
- Symptom relief
Medication trial with titration should be initiated. Treatment is empirical and may require switching or addition of a different category, if one medication is not effective. Botulinum toxin injection is considered in case of significant bruxism, opisthotonus, or abnormal posturing. In case of significant bruxism, initiate dental consultation for mouth piece to protect teeth.
- Rehabilitation strategies intended to stabilize or optimize function or prepare for further interventions at later disease stages. Resting splint and passive range of motion for prevention of joint contractures. Frequent position changes for prevention of decubitus ulcer. Control over or prevention of noxious stimulation in the environment.
- Secondary prevention and disease management strategies
Continue passive range of motion and position changes to prevent decubitus ulcer, deep vein thrombosis, joint contractures and heterotopic ossification. When medications fail to ameliorate symptoms, intrathecal baclofen can be considered.
- Symptom relief: as above.
- Rehabilitation strategies intended to optimize function:
As long as vital signs are unstable, only minimal rehabilitative intervention is feasible, with monitoring of vital signs. Passive range of motion should be continued.
- Continue treatment as in subacute phase. As vital signs stabilize, increase mobility; from simple activity (sitting up, standing at tilt table) with monitoring of vital signs. Initiate aggressive treatment for joint contractures or dystonia.
Coordination of care
Close interdisciplinary communication that includes the acute intensive care physician is crucial for optimizing management.
Patient & family education
Family education is important to decrease noxious stimulation and help with maintaining good positioning to prevent joint contractures and decubitus ulcers.
Measurement of Patient Outcomes
Long term outcome is controversial. The outcomes measured by GOS (Glasgow outcome scale) at 6 and 12 months after brain injury reported poor5,15. However, comparison using the GOS16 as well as FIM (functional independent measure) and DRS (disability rating scale)17 showed that short-term prognosis is poor, but long term outcome was not different from brain injury without CMAD. The long term outcome of the children with history of CMAD showed longer hospital stay and lower WeeFIM scores than children without history of CMAD, but there was no report about the severity difference between the two groups18.
Translation into practice
Significant gastroesophageal reflux can be one of noxious stimuli escalating dystonic posturing, and vice versa. High dose of anti-reflux medications can improve symptoms of CMAD.
4. CUTTING EDGE/EMERGING AND UNIQUE CONCEPTS AND PRACTICE
Cutting edge concepts and practice
For focal dystonia (bruxism or opisthotonus), botulinum toxin injection is indicated. For bruxism, key target muscles are bilateral masseter and temporalis (if approachable, pterygoid muscles are to be targeted). For severe opisthotonus, key target muscles are paraspinal muscles.
5. GAPS IN THE EVIDENCE-BASED KNOWLEDGE
Gaps in the evidence-based knowledge
There is a paucity of evidence supporting any single treatment that sufficiently ameliorates the condition. Reportedly, CMAD was successfully managed with hyperbaric oxygen therapy in six cases19, but all patients received the therapy at 30 days after the brain injury and the diagnosis of CMAD was questionable.
- Rabinstein AA, Benarroch EE. Treatment of paroxysmal sympathetic hyperactivity. Curr Treat Options Neurol. 2008;10:151–157.
- Perkes IE, Menon DK, Nott MT, Baguley IJ. Paroxysmal sympathetic hyperactivity after acquired brain injury: a review of diagnostic criteria. Brain Inj. 2011; 25(10):925-932.
- Rabinstein AA (2). Paroxysmal sympathetic hyperactivity in the neurological intensive care unit. Neurol Res. 2007;29:680–682.
- Krach LE, Kriel RL, Morris WF, Warhol BL, Luxenberg MG. Central autonomic dysfunction following acquired brain injury in children. Neurorehabil Neural Repair. 1997;11:41–45.
- Lv L-Q, Hou L-J, Yu M-K, Qi X-Q, Chen H-R, Chen J-X, Hu G-H, Luo C, Lu Y-C. Prognostic influence and magnetic resonance imaging findings in paroxysmal sympathetic hyperactivity after severe traumatic brain injury. J Neurotrauma. 2010;27:1945-1950.
- Pranzatelli MR, Pavlakis SG, Gould RJ, De Vivo DC. Hypothalamic midbrain dysregulation syndrome: hypertension, hyperthermia, hyperventilation, and decerebration. J Child Neurol. 1991;6:115-122.
- Baguley IJ, Heriseanu RE, Cameron ID, Nott MT, Slewa-Younan S. A critical review of the pathophysiology of dysautonomia following traumatic brain injury. Neurocrit Care. 2008;8:293-300.
- Hughes JD; Rabinstein AA. Early diagnosis of paroxysmal sympathetic hyperactivity in the ICU. Neurocrit Care. 2014; 20(3):454-459.
- Mehta NM, Bechard LJ, Leavitt K, Duggan C. Severe weight loss and hypermetabolic paroxysmal dysautonomia following hypoxic ischemic brain injury: the role of indirect calorimetry in the intensive care unit. JPEN. 2008; 32(3):281-284.
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- Lambert G, Naredi S, Ede´n E, Rydenhag B, Friberg P. Sympathetic nervous activation following subarachnoid hemorrhage: influence of intravenous clonidine. Acta Anaesthesiol Scand. 2002; 46:160–165.
- Baguley IJ, Cameron ID, Green AM, Slewa-Younan S, Marosszeky JE, Gurka J. Pharmacological management of dysautonomia following traumatic brain injury. Brain Inj. 2004;18:409-417.
- Perkes I, Baguley IJ, Nott MT, Menon DK. A review of paroxysmal sympathetic hyperactivity after acquired brain injury. Ann Neurol. 2010; 68(2): 126-135.
- Hendricks HT, Heeren AH, Vos PE. Dysautonomia after severe traumatic brain injury. Eur J Neurol. 2010;17:1172-1177.
- Fernandez-Ortega JF, Prieto-Palomino MA, Garcia-Caballero M, Galeas-Lopez JL, Quesada-Garcia G, Baguley IJ. Paroxysmal sympathetic hyperactivity after traumatic brain injury: clinical and prognostic implications. J Neurotrauma. 2012; 29(7):1364-1370.
- Laxe S, Terre R, Leon D, Bernabeu M. How does dysautonomia influence the outcome of traumatic brain injured patients admitted in a neurorehabilitation unit? Brain Inj. 2013; 27(12):1383-1387.
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- Lv LQ, Hou LJ, Yu MK, Ding XH, Qi XQ, Lu YC. Hyperbaric oxygen therapy in the management of paroxysmal sympathetic hyperactivity after severe traumatic brain injury: a report of 6 cases. Arch Physical Med Rehabil. 2011; 92(9):1515-1518.
Original Version of Topic
Chong Tae Kim, MD. Cerebrally Mediated Autonomic Dysfunction. 11/10/2011.
Chong Tae Kim, MD
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