The excitatory:inhibitory ratio model (EIR model): An integrative explanation of acute autonomic overactivity syndromes

doi:10.1016/j.mehy.2007.04.037

Medical Hypotheses

Volume 70, Issue 1, 2008, Pages 26-35

https://doi.org/10.1016/j.mehy.2007.04.037 Get rights and content

Summary

Numerous medical conditions present with acute and severe autonomic and muscular overactivity. These syndromes include Neuroleptic Malignant Syndrome, Serotonin Syndrome, Dysautonomia (or paroxysmal sympathetic storms) following acquired brain injury, Autonomic Dysreflexia, Parkinsonian-Hyperpyrexia Syndrome, Malignant Catatonia, intrathecal baclofen withdrawal, Malignant Hyperthermia, Stiff Man Syndrome and Irukandji Syndrome. In their worst forms, each of these syndromes are relatively rare, are treated by different medical specialties and show widely varying pathophysiology. Most are considered to be medical emergencies and share significant mortality rates. Previous authors have noted similarities between some of these conditions, prompting the suggestion that a single common mechanism may underlie their clinical presentation. However, the development of such an integrative model has not occurred.

This paper presents a short review of the clinical syndromes, grouped by the location of pathology and mechanism of action. From this background, an integrative framework termed the excitatory:inhibitory ratio (EIR) model is presented. The EIR model consists of two inter-related networks operating at spinal and brainstem levels. The model is evaluated against pre-clinical scientific research, known pathways, each disorder’s pathophysiology (where this is known) and variable severity, and used to explain the reasons behind the efficacy of current treatment regimes. Circumstantial evidence for an expanded aetiology for Malignant Hyperthermia is provided and generic treatment strategies for a number of other conditions are suggested. Finally, minor modifications to this model provide a basis to begin to explain less severe, regional “overlap” syndromes.

Section snippets

Background

Numerous acute medical conditions present with severe autonomic nervous system (ANS) and muscular overactivity. These conditions include Neuroleptic Malignant Syndrome, Serotonin Syndrome, Dysautonomia following acquired brain injury (also known as paroxysmal sympathetic storm), Autonomic Dysreflexia, acute drug withdrawal states (in particular intrathecal baclofen and dopaminergic agents), Malignant Catatonia, Malignant Hyperthermia and Stiff Man Syndrome. In addition, similar clinical

The model

In the model, the common symptoms of these syndromes, the motor and sympathetic overactivity (hereafter termed the efferent features), are explained by two parameters acting at a spinal cord level with additional modulation from higher centres. These parameters are firstly the extent and the rate of increase in the ratio between excitatory and inhibitory influences modulating spinal afferents (the excitatory:inhibitory ratio (EIR)) and secondly the individual’s tendency to develop an

Evidence for pathways

Identifying a spinal pathway for this model requires a minor extension of lower limb flexor withdrawal or RIII reflex pathways (see Sandrini for review) [36]. This is a well-studied, highly reproducible, polysynaptic and multisegmental nociceptive reflex of the lower limb. It is both stimulated and inhibited by all levels of the central nervous system and has known links with the ANS. While best studied in the lower limb, equivalent pathways are also found in the upper limbs. While the reflex

Lesion location

The EIR model readily explains the site of pathophysiology of each overlap syndrome. The reversible neurotransmitter group (that is, NMS, SS, etc.) presynaptically increase BEIR, with the result of reducing the SEIR threshold, thereby priming the individual’s spinal cord to over-react to afferent stimuli. The severity of the resultant syndrome is then determined by the patient’s allodynic tendency, with only a small minority developing the most severe efferent features. This model explains the

Neurotransmitters and medications

Knowledge derived from the overlap conditions infers a regulatory framework for the EIR mechanism. The reversible neurotransmitter syndromes suggest dopamine increases the inhibitory drive from the BEIR whereas other inputs, potentially including serotonin, reduce this inhibitory output. At the spinal level, overlap syndromes suggest Na⁺ and Ca⁺⁺ channels and abnormal RyR1 increase excitation (suggested by AD, IS neurotoxin, allodynic sensitisation and RyR1 in axonal injury). On the inhibitory

Implications and future research

The EIR model generates a large number of testable hypotheses across each of the overlap conditions. Central among these is the concept of the primacy of spinal cord dyscontrol as the common underlying cause of the overlap conditions. The model and other evidence suggests potential value in revisiting the role of abnormal RyR receptor’s and the possibility of a combined neurological/muscle aetiology for MH. Clinical similarities between IS and MH point to the possibility of a role for RyR

Conclusion

The EIR model serves to explain disparate but overlapping disease states within a single unifying framework, the principles of which centre around the loss of control of normal spinal cord mechanisms. The model incorporates and potentially extends beliefs regarding each disorder’s pathophysiology and observed treatment responses. The model also satisfies the basic tenet of Occam’s razor, in that the explanatory mechanism is relatively simple despite the apparent complexities of the various

References (54)

M. Onofrj et al.
Acute akinesia in Parkinson disease
Neurology
(2005)
C.M. Kipps et al.
Movement disorder emergencies
Movement Disord
(2005)
K.L. Philbrick et al.
Malignant Catatonia
J Neuropsych Clin Neurosci
(1994)
E.W. Boyer et al.
The serotonin syndrome
New Eng J Med
(2005)
G.K. Isbister et al.
The pathophysiology of serotonin toxicity in animals and humans: implications for diagnosis and treatment
Clin Neuropharmacol
(2005)
R.A. Ener et al.
Serotonin syndrome and other serotonergic disorders
Pain Med
(2003)
I.J. Baguley et al.
Dysautonomia after traumatic brain injury: a forgotten syndrome?
J Neurol Neurosurg Psychiat
(1999)
I.J. Baguley et al.
Dysautonomia and heart rate variability following severe traumatic brain injury
Brain Inj
(2006)
M.R. Pranzatelli et al.
Hypothalamic-midbrain dysregulation syndrome: hypertension, hyperthermia, hyperventilation, and decerebration
J Child Neurol
(1991)
G.E. Soloman
Diencephalic autonomic epilepsy caused by a neoplasm
J Pediatrics
(1973)

W.T. Talman et al.

A hyperthermic syndrome in two subjects with acute hydrocephalus

Arch Neurol

(1988)

R. Becker et al.

Intrathecal baclofen alleviates autonomic dysfunction in severe brain injury

J Clin Neurosci

(2000)

E. Rossitch et al.

The autonomic dysfunction syndrome: aetiology and treatment

Br J Neurosurg

(1988)

R.R. Thorley et al.

Acute hypothalamic instability in traumatic brain injury: a case report

Arch Phys Med Rehabil

(2001)

I.J. Baguley et al.

Pharmacological management of Dysautonomia following traumatic brain injury

Brain Inj

(2004)

R. Wilkinson et al.

Neuroleptic malignant syndrome induced by haloperidol following traumatic brain injury

Brain Inj

(1999)

R.J. Coffey et al.

Abrupt withdrawal from intrathecal baclofen: recognition and management of a potentially life-threatening syndrome

Arch Phys Med Rehabil

(2002)

I. Mohammed et al.

Intrathecal baclofen withdrawal syndrome – a life-threatening complication of baclofen pump: a case report

BMC Clin Pharmacol

(2004)

D. Guillaume et al.

A clinical study of intrathecal baclofen using a programmable pump for intractable spasticity

Arch Phys Med Rehabil

(2005)

E. Cuny et al.

Dysautonomia syndrome in the acute recovery phase after traumatic brain injury: relief with intrathecal Baclofen therapy

Brain Inj

(2001)

L.B. Green et al.

Death after acute withdrawal of intrathecal baclofen: case report and literature review

Arch Phys Med Rehabil

(1999)

D. Bensmail et al.

Effect of intrathecal baclofen on sleep and respiratory function in patients with spasticity

Neurology

(2006)

K.D. Winkel et al.

Cardiovascular actions of the venom from the Irukandji (Carukia barnesi) jellyfish: effects in human, rat and guinea-pig tissues in vitro and in pigs in vitro

Clin Exp Pharmacol Physiol

(2005)

C.J. Macrokanis et al.

Irukandji syndrome in northern Western Australia: an emerging health problem

Med J Austral

(2004)

P.J. Fenner et al.

Fatal envenomation by jellyfish causing Irukandji syndrome

Med J Austral

(2002)

R.W. Teasell et al.

Cardiovascular consequences of loss of supraspinal control of the sympathetic nervous system after spinal cord injury

Arch Phys Med Rehabil

(2000)

L.C. Weaver et al.

Autonomic dysreflexia after spinal cord injury: central mechanisms and strategies for prevention

Prog Brain Res

(2006)

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Paroxysmal sympathetic hyperactivity (PSH) is a life-threatening neurological emergency associated with severe brain injury. Stroke-related PSH, particularly post-aneurysmal subarachnoid hemorrhage (aSAH) PSH, has been relatively understudied and is often misdiagnosed as an aSAH-related hyperadrenergic crisis. This study aims to clarify the feature of stroke-related PSH.
This study discusses the case of a patient with post-aSAH PSH and identifies 19 articles (25 cases) on stroke-related PSH by searching the PubMed database from 1980 to 2021.
In the total cohort, 15 (60.0%) patients were male and the average age was 40.1 ± 16.6 years. The primary diagnoses included intracranial hemorrhage (13 cases, 52.0%), cerebral infarction (7 cases, 28.0%), subarachnoid hemorrhage (4 cases, 16.0%), and intraventricular hemorrhage (1 case, 4.0%). The sites of stroke damage were predominantly the cerebral lobe (10 cases, 40.0%), basal ganglia (8 cases, 32.0%), and the pons (4 cases, 16.0%). The median time of PSH onset after admission was 5 (1–180) days. Most cases employed combination therapy with sedation drugs, beta-blockers, gabapentin, and clonidine. On the Glasgow Outcome Scale, outcomes included death (4 cases, 21.1%), vegetative state (2 cases, 10.5%), severe disability (7 cases, 36.8%), and in only one case (5.3%) was a good recovery noted.
The clinical features and treatment of post-aSAH PSH differed from those of aSAH-related hyperadrenergic crises. Early diagnosis and treatment can prevent severe complications. PSH should be acknowledged as a potential complication of aSAH. Differential diagnosis can aid in developing individualized treatment plans and improving patient prognosis.
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Su aparición se relaciona con aumento en la mortalidad y un pobre resultado neurológico al alta, con importantes secuelas neurológicas; de ahí que realizar un diagnóstico oportuno y dar tratamiento pertinente jueguen un rol crucial en el pronóstico de los pacientes con lesión neurológica aguda.
Históricamente, la literatura científica al respecto ha sido escasa y heterogénea; su falta de consenso abarca aspectos como su definición, los criterios diagnósticos, la certeza de su epidemiología, pasando por una fisiopatología que no ha sido del todo dilucidada, y por ende aproximaciones terapéuticas hipotéticas. Se desarrolló una estrategia de revisión narrativa. La búsqueda en siete bases de datos bibliográficas, restringidas a publicaciones en inglés y en español, identificó 98 artículos relacionados con los términos de interés, seleccionando finalmente 18 con evidencia de estudios de anatomofisiopatología, manejos farmacológicos y no farmacológicos, así como estudios de consenso y guías de manejo. En conclusión, esta revisión tiene como objetivos desarrollar el conocimiento por parte del intensivista de esta patología para posteriormente lograr un diagnóstico temprano y una intervención terapéutica oportuna.
Paroxysmal sympathetic hyperactivity occurs in patients suffering from some type of acute neurological condition, traumatic brain injury in the main, although this is not its sole aetiology. The increase in sympathetic activity in these patients will generate increased heart rate, blood pressure, and respiratory rate, in parallel with increased parasympathetic activity diaphoresis and hyperthermia; in many cases they occur simultaneously. The clinical syndromes that occur after severe traumatic brain injury have been attributed to structural damage with loss of autonomic response regulation mechanisms. Anatomically it has been proposed that these centres may be located in the upper part of the brainstem, the diencephalon, the anterior hypothalamus, and other cortical and subcortical centres.
Its onset is related to an increase in mortality and a poor neurological outcome at discharge, with important neurological sequelae. Therefore, timely diagnosis and appropriate treatment play a crucial role in the prognosis of patients with acute neurological injury.
Historically, the scientific literature on the subject has been heterogeneous; its lack of consensus covers aspects such as its definition, diagnostic criteria, the certainty of its epidemiology, including a pathophysiology that has not been fully clarified, and therefore hypothetical therapeutic approaches. A narrative review strategy was developed. A search in seven bibliographic databases, restricted to English and Spanish, identified 18 articles related to the terms of interest, showing studies on pathophysiology, pharmacological and non-pharmacological management, as well as consensus studies and management guidelines. In conclusion, this review aims to develop the intensivist's knowledge of this pathology to achieve early diagnosis and timely therapeutic intervention.
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The systemic cardiovascular effects of major trauma, especially neurotrauma, contribute to death and permanent disability in trauma patients and treatments are needed to improve outcomes. In some trauma patients, dysfunction of the autonomic nervous system produces a state of adrenergic overstimulation, causing either a sustained elevation in catecholamines (sympathetic storm) or oscillating bursts of paroxysmal sympathetic hyperactivity. Trauma can also activate innate immune responses that release cytokines and damage-associated molecular patterns into the circulation. This combination of altered autonomic nervous system function and widespread systemic inflammation produces secondary cardiovascular injury, including hypertension, damage to cardiac tissue, vascular endothelial dysfunction, coagulopathy and multiorgan failure. The gasotransmitters nitric oxide (NO) and hydrogen sulfide (H₂S) are small gaseous molecules with potent effects on vascular tone regulation. Exogenous NO (inhaled) has potential therapeutic benefit in cardio-cerebrovascular diseases, but limited data suggests potential efficacy in traumatic brain injury (TBI). H₂S is a modulator of NO signaling and autonomic nervous system function that has also been used as a drug for cardio-cerebrovascular diseases. The inhaled gases NO and H₂S are potential treatments to restore cardio-cerebrovascular function in the post-trauma period.
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Se describe el caso clínico de una paciente de 59 años con antecedentes de trastorno bipolar, ingresada por el servicio de medicina interna por un episodio de crisis convulsiva. Durante la hospitalización, la paciente presentó un importante deterioro clínico, marcado estupor y síntomas de catatonía. Una vez descartadas etiologías neurológicas y metabólicas de la alteración del estado de conciencia, se inició el tratamiento farmacológico con altas dosis de lorazepam. El cuadro clínico de la paciente evolucionó favorablemente con una remisión clínica completa.
El diagnóstico de catatonía constituye un reto tanto para médicos internistas como psiquiatras por su presentación clínica. Con el reporte de este caso clínico se desea enfatizar la importancia de considerar al síndrome catatónico en nuestros diagnósticos diferenciales en pacientes con alteración del estado de conciencia.

View all citing articles on Scopus

^☆: This work resulted in part from a project funded by the Motor Accidents Authority of New South Wales, Australia.

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The excitatory:inhibitory ratio model (EIR model): An integrative explanation of acute autonomic overactivity syndromes☆

Summary

Section snippets

Background

The model

Evidence for pathways

Lesion location

Neurotransmitters and medications

Implications and future research

Conclusion

Acute akinesia in Parkinson disease

Neurology

Movement disorder emergencies

Movement Disord

Malignant Catatonia

J Neuropsych Clin Neurosci

The serotonin syndrome

New Eng J Med

The pathophysiology of serotonin toxicity in animals and humans: implications for diagnosis and treatment

Clin Neuropharmacol

Serotonin syndrome and other serotonergic disorders

Pain Med

Dysautonomia after traumatic brain injury: a forgotten syndrome?

J Neurol Neurosurg Psychiat

Dysautonomia and heart rate variability following severe traumatic brain injury

Brain Inj

Hypothalamic-midbrain dysregulation syndrome: hypertension, hyperthermia, hyperventilation, and decerebration

J Child Neurol

Diencephalic autonomic epilepsy caused by a neoplasm

J Pediatrics

A hyperthermic syndrome in two subjects with acute hydrocephalus

Arch Neurol

Intrathecal baclofen alleviates autonomic dysfunction in severe brain injury

J Clin Neurosci

The autonomic dysfunction syndrome: aetiology and treatment

Br J Neurosurg

Acute hypothalamic instability in traumatic brain injury: a case report

Arch Phys Med Rehabil

Pharmacological management of Dysautonomia following traumatic brain injury

Brain Inj

Neuroleptic malignant syndrome induced by haloperidol following traumatic brain injury

Brain Inj

Abrupt withdrawal from intrathecal baclofen: recognition and management of a potentially life-threatening syndrome

Arch Phys Med Rehabil

Intrathecal baclofen withdrawal syndrome – a life-threatening complication of baclofen pump: a case report

BMC Clin Pharmacol

A clinical study of intrathecal baclofen using a programmable pump for intractable spasticity

Arch Phys Med Rehabil

Dysautonomia syndrome in the acute recovery phase after traumatic brain injury: relief with intrathecal Baclofen therapy

Brain Inj

Death after acute withdrawal of intrathecal baclofen: case report and literature review

Arch Phys Med Rehabil

Effect of intrathecal baclofen on sleep and respiratory function in patients with spasticity

Neurology

Cardiovascular actions of the venom from the Irukandji (Carukia barnesi) jellyfish: effects in human, rat and guinea-pig tissues in vitro and in pigs in vitro

Clin Exp Pharmacol Physiol

Irukandji syndrome in northern Western Australia: an emerging health problem

Med J Austral

Fatal envenomation by jellyfish causing Irukandji syndrome

Med J Austral

Cardiovascular consequences of loss of supraspinal control of the sympathetic nervous system after spinal cord injury

Arch Phys Med Rehabil

Autonomic dysreflexia after spinal cord injury: central mechanisms and strategies for prevention

Prog Brain Res