Handbook of Clinical Neurology, Vol. 119 (3rd series) Neurologic Aspects of Systemic Disease Part I Jose Biller and Jose M. Ferro, Editors © 2014 Elsevier B.V. All rights reserved

Chapter 17

Breathing and the nervous system MIAN ZAIN URFY AND JOSE I. SUAREZ* Department of Neurology, Baylor College of Medicine, Houston, TX, USA

INTRODUCTION Breathing is a complex phenomenon requiring the complex interaction of the central and peripheral nervous systems, mechanical and chemical receptors, and respiratory system. The Roman physician Galen (AD 131–201) was the first to note that gladiators injured below the neck continued to breathe, whereas those with injuries above the neck did not (Benditt, 2006). No major further advances took place until almost 2000 years later, when John Mayow, an English physiologist, in 1668, described the lungs with air-filled cavity driven by negative inspiratory force. Subsequently, in the 1800s, Hering and Breuer discovered mechanoreceptors for reflex control of inspiration and expiration. Later on, the discovery of oxygen (O2) and carbon dioxide (CO2), coupled with the works of John Scott Haldane and Joseph Priestley, elucidated their chemical control of breathing by central and peripheral receptors (Haymaker, 1953). It is now evident that the nervous system plays a major role in the control of volitional and involuntary breathing and that various disease states such as stroke, multiple sclerosis, and tumors can result in various respiratory abnormalities. Although it is still incompletely understood, research continues to add to our knowledge regarding the anatomy and physiology of central respiratory control. In this chapter we will present an overview of the underlying anatomic and physiologic principles of breathing and ventilation control as it is currently understood. We will also delve into some of the pathophysiologic mechanisms of abnormal breathing in neurologic disorders.

NEUROANATOMY OF RESPIRATORY CONTROL

postulated that apart from involuntary subcortical control, there exist extensive cortical neural networks to exert voluntary control of breathing. Previous studies using electrical stimulation, mainly in cats, dogs, and monkeys, showed widespread cortical involvement in voluntary control (Bianchi et al., 1995). Recent advances in positron emission tomography (PET) and functional magnetic resonance imaging (fMRI) have further provided evidence for this postulate. Breathing has been shown to activate widespread bilateral cortical regions involving, but not limited to, the superior motor cortex, the supplementary motor cortex, and the premotor cortex. The extent of bilateral cortical representation remains debatable. Whereas previous transcranial magnetic stimulation and electrical stimulation showed bilateral involvement, fMRI and PET studies conducted recently showed lateralization towards the left hemisphere (Fink et al., 1996; Evans et al., 1999). Apart from motor cortices, there was also activation of the inferolateral sensorimotor cortex. It should be noted that transection of suprapontine respiratory circuitry does not abolish respiratory rhythm; however, it seems to be important in regulating it under various physiologic conditions including hypoxia, exercise, sleep, and arousal (Honda and Tani, 1999). Cortex has extensive connections with caudal hypothalamus as well as basal ganglia. It mainly appears to decrease rate and increase depth of ventilation, as is evident from studies on cat (Horn and Waldrop, 1994). The exact mechanism remains unknown. Further in-depth investigation using breath-to-breath analysis employing physiologic methods would shed more light on our understanding of the volitional control of breathing.

Cortical control of breathing

Subcortical and brainstem control of breathing

Breathing centers in the brain are now believed to be present in the cortex (voluntary) and the brainstem (involuntary) (Bolton et al., 2004) (see Fig. 17.1). It has long been

The brainstem respiratory network consists of three groups of nuclei present in the pons and the medulla: (1) the pontine respiratory group (pneumotaxic center);

*Correspondence to: Jose I. Suarez, M.D., Professor of Neurology, Department of Neurology, Baylor College of Medicine, One Baylor Plaza, NB:320, Houston, TX 77030, USA. Tel: þ1-713-798-8472, Fax: þ1-713-798-3091, E-mail: [email protected]

CEREBRAL CORTEX C

BASAL GANGLIA, HYPOTHALAMUS

O

P

R

A

T

T

I

H

C

W

A

A

SUB CORTICAL L

C O R T I C

Y

O

S

S P I N A L

BRAIN STEM RESPIRATORY NUCLEI (PNUMOTAXIC CENTER, DRG, VRG)

T

RETICULOSPINAL

R A

T

C

R

T

A C T

PETROSAL GANGLION

ANTERIOR HORN CELLS (SPINAL CORD)

NODOSE GANGLION

CN IX

CN

CN

X

V, VII,

CB

AB

IX, X, X1

PERIPHERAL CHEMORECEPTORS

UPPER AIRWAY RECEPTORS NASAL (SNEEZE, DIVING REFLEX) EPIPHARYNGEAL (ASPIRATION REFLEX)

I N T E R C O S T A L

P H R E N I C

N E R V E

N E R V E S

LUNGS

C2 T1-11 C5

PHARYNGEAL (SWALLOWING) LARYNGEAL (COUGH, APNEA)

CN X

C-FIBER ENDINGS, HERING-BREUER INFLATION, DEFLATION REFLEX

Fig. 17.1. Respiratory feedback loop involving cortical (volitional) and subcortical (automatic) connections. Corticospinal tract carries input from cortex, whereas reticulospinal tract (RST) carries input from brainstem nuclei to anterior horn cells in spinal cord. Brainstem nuclei include pneumotaxic center, dorsal respiratory group (DRG), and ventral respiratory group (VRG). Feedback from lungs stretch receptors (Hering–Breuer reflex) as well neural receptors is conveyed through vagal nerve to brainstem. Upper airway receptors as shown also provide extensive input from cranial nerves V, VII, IX, X, XI, and XII. Peripheral chemoreception involves carotid (CB) and aortic bodies (AB), and carries signal through IX and X nerves respectively to nucleus tractus solitarius through relay ganglions. Central chemoreception is mainly serum CO2- and pH-dependent located in brainstem respiratory group of nuclei.

BREATHING AND THE NERVOUS SYSTEM (2) the dorsal respiratory group (DRG); and, (3) the ventral respiratory group (VRG) (Feldman, 1986; Bianchi et al., 1995; Duffin et al., 1995; Blessing, 1997) (see Fig. 17.1). The pontine respiratory group is located in the dorsal lateral pons and contains both inspiratory and expiratory neurons. It includes the nucleus parabranchialis medialis and the K€ olliker-Fuse nucleus. It appears to exert fine modulation of respiration and experimental lesions of this center prolong inspiration (Richter and Spyer, 2001). However, the pontine respiratory group does not seem to be necessary for basic respiratory rhythm generation (McCrimmon et al., 2000). The two groups of neurons present in the medulla, DRG and VRG, are essential for basic respiration generation. DRG is anatomically located in the ventrolateral subnucleus of the nucleus of the tractus solitarius (NTS) and contains inspiratory neurons receiving input from the vagal nerves (Bianchi et al., 1995). VRG neurons are present in the ventrolateral medulla and contain the B€ otzinger and pre-B€ otzinger Complex of neurons necessary for respiratory rhythm generation. Experimental lesions of theses complexes have shown to abolish normal respiratory rhythm generation (McCrimmon et al., 2000; Del Negro et al., 2002; Doi and Ramirez, 2008). Nerve impulses from the cortex and the brainstem reach the spinal cord via the corticospinal and the reticulospinal tracts for voluntary and involuntary control, respectively (Benditt 2006; Bolton et al., 2004). These axons synapse onto anterior horn cells. It also is important to mention that there are extensive interactions between the autonomic cardiovascular and respiratory responses. These involve, but are not limited to, modulations from the NTS and the ventrolateral medulla. The NTS receives inputs from baroreceptors and other arterial receptors and is involved in the integration of both responses. Inhibition of central cardiovagal neurons during inspiration and excitation during expiration provides the basis for sinus arrhythmia (Spyer et al., 1994). The basal ganglia and caudal hypothalamus also play a role in control of respiration. The caudal hypothalamus has reciprocal connections with motor cortex as well as the periaqueductal area and ventrolateral medulla (Yeh et al., 1997; Eric and Tony, 1998). It provides excitatory input on brainstem respiratory centers as evidenced by studies using barbiturates and/or electrical stimulation of the hypothalamus (Keller, 1960; Dean and Boulant, 1989). Furthermore, investigators have found that sectioning of the brain rostral to the diencephalon increases ventilation, while a mid-collicular lesion has no effect on ventilation (Eric and Tony, 1998). Electrical stimulation of the basal ganglia elicits a locus-dependent response in animal models. For instance, in cats, stimulation of the external portion of the globus pallidus results in increased

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respiratory rate, whereas stimulation of the internal segment of the globus pallidus has the opposite effect. These effects were seen to be abolished after neurotoxic damage of the basal ganglia (Angya´n and Angya´n, 2001).

PHYSIOLOGIC CONTROL OF BREATHING AND RHYTHM GENERATION Rhythm generation The central nervous system controls breathing through its effects on lung volumes, and inspiration and expiration duration. Extensive in vivo and in vitro studies conducted in the last few decades have helped to establish the basic respiratory control as rhythm generation (Doi and Ramirez, 2008). It is now widely believed that there is a rhythm-generating group of neurons to maintain the basic control of breathing. They also seem to have cortical control of breathing but mainly act automatically. The B€otzinger and pre-B€otzinger groups of nuclei have been found to have pacemaker activity. It is generally believed that this pattern resulting in rhythm generation consists of three phases: inspiration, early expiration and late expiration, even though respiration is a twophase process consisting of inspiration and expiration (McCrimmon et al., 2000; Ramirez et al., 2002; Bolton et al., 2004). This pacemaker activity is in turn influenced by the sensory integration of chemical and mechanical feedback stemming from peripheral receptors. Several neurotransmitters, including GABA, glycine, GABA and neurokinin-1, appear to play a major role in modulating this response (Murakoshi et al., 1985).

Pacemaker neurons The B€otzinger and pre-B€otzinger neurons located in the VRG appear to generate pacemaker activity through burst neurons. The exact mechanism leading to this pacemaker activity and how these neurons are influenced via multiple stimuli is poorly understood. There is now increasing evidence that these pacemaker cells have differential properties and contain multiple different types of ionic channels (Smith et al., 1991; Nogues et al., 2002). Onimaru et al. (1997) have classified six different types of pacemaker cells in rats labeled as preinspiratory (Pre-1), three inspiratory (Insp I, II, III), and two expiratory neurons (Exp I, II), based on their postsynaptic potentials (see Fig. 17.2). These groups of neurons have different type of channels (calcium, chloride, and sodium) proven through differential pharmacologic blockade. They also appear to have differential response under varying concentrations of blood gases. For example, in experimental models using calciumsensitive fluorescent dye, these groups of neurons have shown periodic increases in intracellular calcium mediated

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Fig. 17.2. Classes of respiratory neurons in the brainstem–spinal cord preparation. (A) Preinspiratory (Pre-I) neurons are characterized by synaptic drive potentials and spike discharge which onset prior to and terminate after cessation of inspiratory spinal (C4) nerve discharge. Cl-mediated IPSPs during the inspiratory phase are a feature of most Pre-I neurons Aa, whereas inhibition is not observed in a subclass of these cells (Ab). Ac and Ad exemplify that the duration of the pre- or postinspiratory activity phase varies between individual cells. (B) Type-I inspiratory (Insp-I) neurons are characterized by spike discharge during C4 burst activity and by subthreshold (Ba) or spike-evoking EPSPs (Bb) within the peri-inspiratory period. Type-III Insp neurons are hyperpolarized by Cl-mediated IPSPs during the peri-inspiratory phase (Bd), whereas peri-inspiratory PSPs are not observed in type-II Insp cells (Bc). (C) Expiratory (Exp) neurons are hyperpolarized by Cl-mediated IPSPs either during the inspiratory (Exp-i, Ca) or the peri-inspiratory (Exp-p-i, Cb) phase. (Reproduced from Onimaru et al., 1997.)

by voltage-sensitive ion channels, as evidenced by regular increase in fluorescence (Onimaru et al., 1996). However, several groups of neurons continue to show burst activity even in the presence of pharmacologic and glutamate blockade (Smith et al., 1995). Further research using various intra- and intercellular physiologic methods is needed to classify this incompletely understood process.

NEUROCHEMICAL CONTROL OF BREATHING The control of breathing involves interaction of both chemical and neural receptors found in the peripheral and central nervous system as well as end organs. The neural receptors are found in upper airway, respiratory

BREATHING AND THE NERVOUS SYSTEM muscles, lungs, and pulmonary vessels (Bolton et al., 2004). These include muscle spindles, and pulmonary stretch receptors responding to changes in lung volumes and thoracic cavity pressure. There have been multiple different types of pulmonary sensory receptors identified including fast and slow adapting (stretch) receptors and C-fiber receptors (J receptors) (Widdicombe, 1982, 2001; Brouns et al., 2012). These receptors detect changes in lung tidal volumes. Slow adapting fibers seem to have a role in inflation reflex and terminate inspiration and prolong expiration (Schelegle, 2003). Fast adapting fibers regulate deflation reflex and mediate deep augmented breaths. C-fiber receptor (J receptors, previously known as juxtapulmonary receptors) stimulation causes reflex increase in breathing rate and is also important in the detection of dyspnea. This J receptor-mediated reflex initially causes apnea followed by rapid, shallow breathing, bradycardia, and hypotension mediated by the vagal nerve. In addition, J receptors also play a role in bronchoconstriction, laryngospasm, airway mucus secretion, and bronchial and nasal vasodilatation (Paintal, 1995; Sant’Ambrogio and Widdicombe, 2001; Widdicombe, 2001). The peripheral chemoreceptors include the carotid and aortic bodies and are primarily sites that respond to changes in PaO2 but they also modulate their activity to PaCO2 and pH changes (Honda and Tani, 1999). Neural firings of these receptors are increased in response to PaO2 decrement and increase in PaCO2 concentration with subsequent decrease in pH. There is evidence to suggest that aortic bodies respond more in infancy whereas carotid bodies respond more in adulthood (Daly and Ungar, 1966; Lahiri et al., 1981; Horn and Waldrop 1994). Impulses through these are carried to the central nervous system respiratory modulators as described in sections of neuroanatomy via cranial nerves IX and X. Carotid bodies and their role in hypoxia-induced hyperventilation have been extensively studied (Gonzalez et al., 1995; Milsom and Burleson, 2007). They are composed of glomus cells (also known as type I) and sustentacular cells (type II). Carotid bodies release multiple neurotransmitters under hypoxic stimulation. Glomus cells are believed to be involved in afferent transduction. In animals, it has been shown experimentally that potassium-related channels contribute to neurotransmitter release and act as oxygen sensors (Prabhakar, 2006). Sustentacular cells act as glial cells. Hypoxic stimulus is then transferred to the brainstem through the vagal nerve. Aortic bodies are less well studied but there is experimental evidence that they respond to changes in oxygen saturation whereas carotid bodies seem to respond to changes in PO2 (Lahiri et al., 1981). These peripheral receptors also mediate exerciserelated ventilator drive and altitude acclimatization (Dempsey and Smith, 1994; Prabhakar et al., 2009). Receptors situated in the central nervous system are more important and crucial in maintaining body pH and

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acid–base balance. They are mostly responsive to CO2 and pH changes. These receptors are present in different areas including the following: the locus ceruleus, the NTS, the midline raphe and ventrolateral quadrant of the medulla (Bianchi et al., 1995; Honda and Tani, 1999; Nattie, 1999; Kara et al., 2003). Increases in CO2 or decreases in pH have been associated with increases in ventilator response by multiple mechanisms even though they are still incompletely understood. These may include increases in conductance of potassium as well as synaptic transmission via several neurotransmitters such as acetylcholine, and glutamate (Nattie, 1999). There is increasing evidence that central respiratory control of breathing is more widespread and may involve suprapontine structures in the hypothalamus, amygdala, and cerebral cortex. Recent fMRI studies have shown that arcuate nucleus firing increases in response to hypercapnia in cats (Honda and Tani, 1999). In addition, it has also been shown that infants who die of sudden infant death syndrome may have depletion of muscarinic receptors in the arcuate nucleus (Kinney, 2009). Studies using PET and fMRI have shown activation of premotor, primary motor, and supplementary motor cortex areas during increased respiratory drive (Horn and Waldrop, 1994). Future studies using physiologic approaches such as PET and fMRI are expected to shed further light on nervous control of breathing.

NEUROLOGIC CONDITIONS AFFECTING BREATHING Various central and peripheral neurologic disorders have been important in elaborating our understanding of breathing. Lesions affecting cerebral cortex, pathways and tracts, nuclei in the hypothalamus, the brainstem, and the spinal cord can lead to various breathing-related issues. Peripheral nervous disorders affecting pre- and postsynaptic receptors and neurotransmitters can also lead to a variety of abnormal breathing patterns (Nogues et al., 2002; Benditt, 2006). Below are some specific examples further elaborating the importance of nervous control and its interaction with the respiratory system at various anatomic levels (Table 17.1).

Diseases affecting the hemispheric cortex, subcortical structures, and brainstem Neurologic insults causing disruption of the pathways from cerebral cortex, corticospinal tracts, or volitional respiratory centers can lead to loss of voluntary control of breathing. These disorders can include ischemic and hemorrhagic strokes, central pontine myelinolysis, head injury, neurodegenerative conditions, and head injury, to name but a few. It is believed that at the brainstem level, the reticulospinal tract conducts information for voluntary control. One particular state where it can be affected

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Table 17.1 Diseases of the central and peripheral nervous systems associated with abnormal breathing Central nervous system diseases associated with abnormal respiration Cerebral cortex Stroke Tumor Dementia Prion disease Epilepsy Infections

Peripheral nervous system conditions associated with abnormal respiration

Brainstem

Basal ganglia

Spinal cord

Motor nerves

Neuromuscular junction

Stroke Neoplasm Multiple system atrophy Encephalitis Multiple sclerosis Central alveolar hypoventilation Infections

Parkinson’s disease Huntington’s chorea Heavy metal poisoning Carbon monooxide poisoning Fahr’s disease

Trauma Demyelinating conditions (multiple sclerosis, Devic’s disease) Syringomyelia Tumor Motor neuron disease Infections

Motor neuron disease Guillian–Barre´ syndrome Diphtheria Critical illness neuropathy Diabetes Acute intermittent porphyria Uremia Iatrogenic Trauma

Myasthenia gravis Lambert-Easton myasthenic syndrome Botulism Neuromuscular blockers Acetylcholinesterase inhibitors Snake venom Shellfish poisoning Scorpion poison

includes the so-called “locked-in syndrome,” where volitional control of breathing is lost and there is complete paralysis except for horizontal or vertical eye muscles due to lesions involving the basis pontis. Diseases affecting the involuntary control of breathing appear more common and can again be affected by all processes resulting in poor volitional control. They may include unilateral or bilateral medullary infarcts, demyelinating conditions such as multiple sclerosis, or even genetic disorders such as central alveolar hypoventilation. One well-known condition is so-called Ondine’s curse, which results from damage to respiratory centers in brainstem. In this disorder, patients do not have symptoms as long as they are awake, but they develop central sleep apnea as soon as they go to sleep from lack of voluntary control of breathing (Moss, 2005). Different breathing patterns have been described associated with various neurologic conditions. Breathing patterns related to coma have been well described in the literature and correlate with nervous system injury at various anatomic levels (Fig. 17.3). Almost all the neurodegenerative diseases at some stage exhibit breathing abnormalities. These include Parkinson’s disease, multiple system atrophy, Huntington’s chorea, and Lewy body dementia among others (Chokroverty et al., 1978; Hardie et al., 1986). Breathing difficulties may represent early features of some of these conditions and can alert a vigilant physician. These patients usually present with sleep-disordered breathing (SDB) (Gaig and Iranzo, 2012). Cell loss of the brainstem nuclei that modulate respiration, and dysfunction of

pharyngeal, laryngeal, and diaphragmatic muscles can increase the risk for SDB in neurodegenerative disorders. Below, we discuss a few commonly encountered neurodegenerative disorders.

PARKINSON’S DISEASE Parkinson’s disease (PD) is a disorder which is characterized by bradykinesia, rigidity, resting tremor, and postural instability. Excessive daytime sleepiness, obstructive sleep apnea (OSA), and upper airway obstruction are more prevalent in PD patients than in the general population (Neu et al., 1967; Shill and Stacy, 2002). Upper airway obstruction is possibly related to chest wall rigidity and hypokinesia. Several factors have been thought to increase risk of OSA in PD patients, including age and central neurodegeneration of respiratory centers (Neu et al., 1967; Apps et al., 1985). Close monitoring of respiratory problems and addressing them can improve PD patients’ quality of life.

MULTISYSTEM ATROPHY Multisystem atrophy (MSA) is another neurodegenerative disorder, presenting as parkinsonism, cerebellar dysfunction, and dysautonomia. Respiratory difficulties can be the presenting feature in this disorder. It can include central and obstructive breathing problems during wakefulness and sleep. Involuntary gasping, irregular breathing, abnormal hypoxic and hypercapnic respiratory responses, respiratory failure and stridor have been observed during wakefulness (Munschauer

BREATHING AND THE NERVOUS SYSTEM

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Fig. 17.3. Abnormal breathing patterns encountered in patients with pathologic lesions (shaded areas) of the central nervous system. (A) Cheyne–Stokes breathing is seen in patients with metabolic encephalopathies and in those with lesions in the forebrain or diencephalon. (B) Central neurogenic hyperventilation is seen in patients with metabolic encephalopathy or upper brainstem tumors. (C) Apneustic breathing is seen in patients with bilateral pontine lesions. (D) Cluster breathing is seen in patients with lesions affecting the pontomedullary junction. (E) Apnea is seen in patients with lesions affecting the VRG in the ventrolateral medulla bilaterally. (Reproduced from Saper, 2000, p. 902, with permission from McGraw-Hill.)

et al., 1990; Sadaoka et al., 1996). While asleep, patients may complain of OSA, central sleep apnea, apneustic breathing, or Cheyne–Stokes breathing as well as nocturnal stridor. In some studies, these abnormalities have been attributed to degeneration of ventral arcuate nucleus and pre-B€ otzinger Complex (Benarroch et al., 2001, 2007). Aggressive management of these respiratory abnormalities can not only improve quality of life but can also be life-saving. For instance, continuous positive airway pressure (CPAP) can be instituted for OSA and tracheostomies for stridor.

ALZHEIMER’S DISEASE Alzheimer’s disease (AD) is the most common cause of dementia. OSA is encountered with increasing frequency in AD patients. The frequency and prevalence of nocturnal breathing abnormalities has been estimated to be high, ranging from 40–70% in AD patients (Vitiello and Borson, 2001). OSA is also thought to further contribute to cognitive decline in AD along with exacerbations of behavioral abnormalities (Bliwise, 1996). Elimination of OSA by CPAP devices has been reported to result in significant and sustained improvement in cognitive functioning and remains an important research area (Ancoli-Israel et al., 2008; Cooke et al., 2009).

AMYOTROPHIC LATERAL SCLEROSIS Amyotrophic lateral sclerosis (ALS) is a devastating neurodegenerative disorder resulting from degeneration of neurons located in the cortex, brainstem nuclei, and ventral horn of the spinal cord. Nocturnal alveolar hypoventilation, central sleep apnea, OSA and mild periodic oxygen desaturation appear to be more prevalent in ALS patients (Labanowski et al., 1996). Loss of motor neurons in the central nervous system leads to upper and lower respiratory tract muscular weakness and predisposes to respiratory failure and infections. Ventilatory failure is the most common cause of death in ALS, and deterioration in pulmonary function predicts mortality (Fallat et al., 1979). Early detection of respiratory dysfunction and noninvasive ventilation (BIPAP) prolongs survival and quality of life (Aboussouan et al., 1997; Bourke et al., 2003, 2006).

Diseases of the spinal cord Spinal cord injuries can invariably affect breathing and result in devastating complications for the patient. It is important to emphasize that the level of spinal cord injury determines the severity of breathing complications. For those patients with lesions affecting C3

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ventilator support is always required, as the diaphragm, which contributes to 70% of inspiration, takes its nerve supply from C3–C5 (Howard et al., 1998). Various disease processes can result in cord injuries, with trauma being the major one. However, demyelinating lesions (multiple sclerosis, Devic’s disease), tumors, and vascular anomalies can also result in damage to the spinal cord. Patients with injuries below C5 may not require mechanical ventilation, whereas those with lesions between C3 and C5 can require various levels of ventilatory support.

Neuromuscular junction disorders and nerves Various motor nerve disorders and pathologies affecting the neuromuscular junction can result in breathing abnormalities. They can include Guillain–Barre´ syndrome (GBS), myasthenia gravis, botulism, neoplastic and paraneoplastic conditions (Polkey et al., 1999; Benditt, 2006). For example, GBS results in demyelination of nerves innervating respiratory muscles, resulting in ineffective saltatory conduction and decreased muscle strength. Myasthenia gravis mostly results from antibody-mediated autoimmune damage of postsynaptic acetylcholine receptors resulting in loss muscle excitation. This again results in muscle weakness. Phrenic nerve dysfunctions are also seen after surgical manipulation following open thoracotomies and open heart surgeries, resulting in paralysis or weakness of diaphragm. It therefore, can lead to profound respiratory muscle weakness and failure to wean from ventilator.

CLINICAL MANIFESTATIONS OF CENTRAL AND PERIPHERAL NERVOUS SYSTEM CONDITIONS Clinical manifestations of central and peripheral nervous system diseases vary considerably depending on the anatomic location and primary disease process. Affected individuals present with signs of upper motor neuron dysfunction (spasticity, hyperreflexia) for injuries above the anterior horn cells in spinal cord. These conditions may be accompanied by sudden onset weakness (stroke), gradual onset weakness (tumors), behavioral changes and tremors (neurodegenerative conditions). Demyelinating lesions usually present with fluctuating and periodic symptoms and are more common in young females. Whereas conditions below or at anterior horn cells (e.g., polio, GBS) may present with lower motor dysfunction (flaccid paralysis, hyporeflexia), neuromuscular junction disorders present with fluctuating weakness which may be exacerbated or improve with physical activity (myasthenia gravis and Lambert–Eaton syndrome, respectively). These patients may also have signs of involvement of other muscular

groups, e.g., diplopia, leg, or arm weakness (Bolton et al., 2004).

Neurogenic pulmonary edema Neurogenic pulmonary edema (NPE) is a life-threatening complication resulting from severe central nervous system injury. It is characterized by pulmonary vascular congestion causing perivascular edema, intra- and extra-alveolar accumulation of protein-rich edema and intra-alveolar hemorrhage (Brambrink and Dick, 1997; Baumann et al., 2007). It has been attributed to multiple factors but the exact mechanism remains uncertain. It is seen in a variety of neurologic insults including head injury, subarachnoid hemorrhage, status epilepticus, intracerebral hemorrhage, and intracranial tumors, as well as postoperatively. It is more common after cerebral hemorrhage than other neurologic insults (Colice et al., 1984). Two different mechanisms have been believed to contribute to the pathophysiology behind NPE: (1) a sudden increase in intracranial pressure (ICP) and (2) localized ischemic insult to brain trigger zones (vasomotor centers, pulmonary input and output locations, including medulla oblongata, area postrema, caudal medulla, NTS). A sudden increase in sympathetic surge leading to a dramatic increase in a-adrenergic catecholaminergic surge most probably leads to NPE. A diagnosis of NPE should be suspected in any head injury patient who suddenly develops dyspnea. Early and appropriate treatment of the underlying neurologic injury is the fundamental treatment along with standard respiratory support depending on clinical severity. Mortality associated with NPE is high, but recovery can be rapid and full if it is detected early and managed appropriately. NPE in brain death patients is the leading cause of lack of pulmonary grafts and transplantation failure (Trulock, 1997).

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