Central neurogenic hyperventilation
Encyclopedia
Hyperventilation
Hyperventilation or overbreathing is the state of breathing faster or deeper than normal, causing excessive expulsion of circulating carbon dioxide. It can result from a psychological state such as a panic attack, from a physiological condition such as metabolic acidosis, can be brought about by...
, like Kussmaul's respirations
Kussmaul breathing
Kussmaul breathing is a deep and labored breathing pattern often associated with severe metabolic acidosis, particularly diabetic ketoacidosis but also renal failure. It is a form of hyperventilation, which is any breathing pattern that reduces carbon dioxide in the blood due to increased rate or...
. CNH is the human body's response to reduced carbon dioxide levels in the blood. This reduction in carbon dioxide is caused by contraction of cranial arteries from damage caused by lesions in the brain stem
Brain stem
In vertebrate anatomy the brainstem is the posterior part of the brain, adjoining and structurally continuous with the spinal cord. The brain stem provides the main motor and sensory innervation to the face and neck via the cranial nerves...
. However, the mechanism by which CNH arises as a result from these lesions is still very poorly understood. Current research has yet to provide an effective means of treatment for the rare number of patients who are diagnosed with this condition.
Discovery
Central neurogenic hyperventilation (CNH) is an extremely rare neurological disorder that was initially reported by Fred PlumFred Plum
Fred Plum was an American neurologist who developed the terms"persistent vegetative state" and "locked-in syndrome" as part of his continuing research on consciousness and comas and care of the comatose....
, MD and August G. Swanson, MD, in 1959. Plum and Swanson described the symptoms of nine comatose patients, defining CNH as a syndrome consisting primarily of elevated arterial oxygen tension, decreased arterial carbon dioxide tension, and progressive tachypnea
Tachypnea
Tachypnea means rapid breathing. Any rate between 12-20 breaths per minute is normal. Tachypnea is a respiration rate greater than 20 breaths per minute. - Distinction from other breathing terms :...
.
Postmortem examination of the nine patients’ brains reported by Plum and Swanson, revealed necrosis of the central pons
Pons
The pons is a structure located on the brain stem, named after the Latin word for "bridge" or the 16th-century Italian anatomist and surgeon Costanzo Varolio . It is superior to the medulla oblongata, inferior to the midbrain, and ventral to the cerebellum. In humans and other bipeds this means it...
in five of the nine patients, and indirect compression of the pons in one additional patient. Their initial findings suggested that lesions in the medial pontine tegmentum
Pontine tegmentum
The pontine tegmentum is a part of the pons of the brain involved in the initiation of REM sleep. It includes the pedunculopontine nucleus and the laterodorsal tegmental nucleus, among others, and is located near the raphe nucleus and the locus ceruleus....
leads to a disruption of cortical inhibitory effects of medullar respiratory center
Respiratory center
The respiratory center is located in the medulla oblongata, which is the lowermost part of the brain stem. The RC receives controlling signals of neural, chemical and hormonal nature and controls the rate and depth of respiratory movements of the diaphragm and other respiratory muscles...
. Plum and Swanson suggested that failure to inhibit the activity of this particular region of the brain
Brain
The brain is the center of the nervous system in all vertebrate and most invertebrate animals—only a few primitive invertebrates such as sponges, jellyfish, sea squirts and starfishes do not have one. It is located in the head, usually close to primary sensory apparatus such as vision, hearing,...
results in continuous stimulation of the respiratory center by the lateral pontile reticular formulation and laterally located descending neural pathway
Neural pathway
A neural pathway, neural tract, or neural face, connects one part of the nervous system with another and usually consists of bundles of elongated, myelin-insulated neurons, known collectively as white matter...
. The destruction of this required negative feedback
Negative feedback
Negative feedback occurs when the output of a system acts to oppose changes to the input of the system, with the result that the changes are attenuated. If the overall feedback of the system is negative, then the system will tend to be stable.- Overview :...
mechanism causes the uncontrollable hyperventilation associated with CNH.
Additional Findings
Subsequent findings revealed CNH can also occur in conscious patients. Patients with tumor-induced CNH remain conscious because the reticular activating systemReticular activating system
The reticular activating system is an area of the brain responsible for regulating arousal and sleep-wake transitions.- History and Etymology :...
of the brain is not affected by the tumor in the early stages of the condition. The condition is considered extremely uncommon, and only 21 additional cases of tumor-inducing CNH were reported up until 2005. Only five of these cases were reported in children. The causes associated with conscious CNH are more varied than originally predicted by Plum and Swanson’s study of comatose patients, although the most commonly reported causes of CNH involve infiltrative glioma
Glioma
A glioma is a type of tumor that starts in the brain or spine. It is called a glioma because it arises from glial cells. The most common site of gliomas is the brain.-By type of cell:...
s and lymphoma
Lymphoma
Lymphoma is a cancer in the lymphatic cells of the immune system. Typically, lymphomas present as a solid tumor of lymphoid cells. Treatment might involve chemotherapy and in some cases radiotherapy and/or bone marrow transplantation, and can be curable depending on the histology, type, and stage...
s of the brainstem and pons.
Although the majority of CNH-inducing tumors are located in close proximity to other medullary homeostatic centers, the physiological changes associated with CNH are restricted to alterations in the control of breathing. Most patients present with normal readings for heart rate and blood pressure, even in the case of severe alkalosis caused by CNH, which indicates that the respiratory center affected by CNH is more sensitive to compression than other areas of the brain.
Diagnosis
For the clinical diagnosis of CNH, it is essential that the symptoms, particularly respiratory alkalosis, persist while the patient is both awake and asleep. The presence of hyperventilation during sleep excludes any possible emotional or psychogenic causes for the sustained hyperventilation. There must also be no evidence of drug or metabolic causes, including cardiac or pulmonary disease, or recent or current use of respiration-stimulating drugs. While a positive diagnosis of CNH in adult cases should be reserved only until all other possible causes of tachypnea have been eliminated, CNH should be suspected in any alert child presenting with unexplained hyperventilation and hypocarbia leading to respiratory alkalosis. Once CNH is determined to be a possible cause of hyperventilation, lesions and their location in the brain are verified using magnetic resonance imagingMagnetic resonance imaging
Magnetic resonance imaging , nuclear magnetic resonance imaging , or magnetic resonance tomography is a medical imaging technique used in radiology to visualize detailed internal structures...
(MRI).
Prognosis
The onset of CNH in all patients regardless of age can be a precursor to ensuing deterioration in patients with infiltrative tumors of the brainstem and medulla. These patients experience prolonged series of CNH before succumbing to the associated deterioration of medullary cardiovascular center, which ultimately results in death. In addition to clinical consequences of a positive CNH diagnosis, sustained hyperventilation also has a marked affect on daily life activities, and may significantly impede a patient’s ability to eat or talk. The persistent hypocarbia, alkalotic pH, and resultant electrolyte disequilibrium may also alter a patient’s mood or mental state. Patients presenting with CNH are often are described as inattentive and anxious.Causes of CNH
Determining the exact cause of CNH has proven to be difficult, specifically because only 21 additional cases have been reported since Plum and Swanson’s initial report of the condition in 1959. These subsequent reports deal only with conscious patients presenting with CNH, though the varied pathophysiologies present in each individual patient makes it nearly impossible to implicate either a particular structural lesion or the destruction of a specific locus as the sole cause of CNH. Compilations of the reports, however, have led to generalized conclusions about the primary role of structural lesions in the initiation of both juvenile and adult cases of CNH.Tumor-Induced CNH in Adults
The majority of adult patients experiencing CNH have clinical histories of infiltrative, expanding tumors of the cortex, primarily involving the brainstem. Over three-quarters of the cases reported since the discovery of CNH by Plum and Swanson had tumors clearly involving the pons, with specific consideration given to pathology of the pontine tegmentumPontine tegmentum
The pontine tegmentum is a part of the pons of the brain involved in the initiation of REM sleep. It includes the pedunculopontine nucleus and the laterodorsal tegmental nucleus, among others, and is located near the raphe nucleus and the locus ceruleus....
. CNH was also reported in patients with tumors affecting the medulla oblongata
Medulla oblongata
The medulla oblongata is the lower half of the brainstem. In discussions of neurology and similar contexts where no ambiguity will result, it is often referred to as simply the medulla...
.
Though a diagnosis of CNH is rarely considered without evidence of brainstem infiltration, there have been other reported cases of CNH not directly involving the pons or medulla. CNH was also reported in cases involving a frontal lobe tumor, an invasive laryngeal carcinoma compressing the midbrain, an extension of tumors of the head and neck into the base of the brain, and thalamic hemorrhage. The manifestation of CNH in patients with these non-brainstem related disorders leads to greater debate about the pathophysiology of CNH and the role of other parts of the brain in the regulation of respiration. At this time, there have been no reported cases of CNH associated with stroke
Stroke
A stroke, previously known medically as a cerebrovascular accident , is the rapidly developing loss of brain function due to disturbance in the blood supply to the brain. This can be due to ischemia caused by blockage , or a hemorrhage...
.
In each case, the nature of the tumor varied, though the two main categories of tumor were classified as either cerebral lymphoma
Lymphoma
Lymphoma is a cancer in the lymphatic cells of the immune system. Typically, lymphomas present as a solid tumor of lymphoid cells. Treatment might involve chemotherapy and in some cases radiotherapy and/or bone marrow transplantation, and can be curable depending on the histology, type, and stage...
s or solid tumors, such as pontine glioma
Glioma
A glioma is a type of tumor that starts in the brain or spine. It is called a glioma because it arises from glial cells. The most common site of gliomas is the brain.-By type of cell:...
s, anaplastic medulloblastoma
Medulloblastoma
Medulloblastoma is a highly malignant primary brain tumor that originates in the cerebellum or posterior fossa.Previously, medulloblastomas were thought to represent a subset of primitive neuroectodermal tumor of the posterior fossa...
, or astrocytoma
Astrocytoma
Astrocytomas are a type of neoplasm of the brain. They originate in a particular kind of glial-cells, star-shaped brain cells in the cerebrum called astrocytes. This type of tumor does not usually spread outside the brain and spinal cord and it does not usually affect other organs...
s.
Particular attention is given to the high incidence of cerebral lymphomas associated with adult CNH. Intracerebral B-cell lymphoma represents less than 1% of all primary malignant tumors of the central nervous system. Infiltration of lymphoma cells into the pons and medulla is the most frequently reported cause of CNH, accounting for half of all CNH-inducing brain tumors, despite its considerable rarity. It has been suggested that these lymphomas are capable of diffusely penetrating the midbrain, without majorly destructing the overall structures.
Tumor-Induced CNH in Children
CNH in children is considerably less common, and only five of the twenty one cases have been documented in children aged 11 and younger. The primary difference between juvenile and adult cases of CNH is the structural identity of the tumors leading to CNH symptoms. Four of the five cases of CNH involving children were associated with solid infiltrative gliomas on the brainstem, while only one case was associated with an apparent lymphoma referred to as microgliomatosis.Non-tumor Induced CNH
There have been only a few reported cases of non-tumor induced CNH, most of which have been successfully treated. Recently, the anticonvulsant drug TopiramateTopiramate
Topiramate is an anticonvulsant drug. It was originally produced by Ortho-McNeil Neurologics and Noramco, Inc., both divisions of the Johnson & Johnson Corporation. This medication was discovered in 1979 by Bruce E. Maryanoff and Joseph F. Gardocki during their research work at McNeil...
induced temporary CNH in patients, which abated after drug use was terminated. Additionally, there has been one reported case of CNH in a patient suffering from multiple sclerosis
Multiple sclerosis
Multiple sclerosis is an inflammatory disease in which the fatty myelin sheaths around the axons of the brain and spinal cord are damaged, leading to demyelination and scarring as well as a broad spectrum of signs and symptoms...
with brainstem lesions. The CNH was considered reversible and was successfully treated with high-dose intravenous methylprednisolone and plasma exchange.
Symptoms
Symptoms of CNH have been observed to vary according to the progression of CNH. The initial symptoms of CNH include a low arterial partial pressure of carbon dioxide, a high or normal arterial partial pressure of oxygen, high arterial pH, and tachypnea. The partial pressure of carbon dioxide has been noted by Yushi et al. to drop as low as 6.7 mmHg, while oxygen saturation remains at 99-100%. Respiratory alkalosis is induced in people affected with CNH, which stimulates the hyperpnea to attempt to compensate the rise of the blood’s pH. Some of the reported cases of CNH claim alkaline cerebral spinal fluid (CSF). However, not all of the cases experience this effect and other cases of CNH have a local increase in the pH surrounding the tumor that causes the condition. The hyperventilation of CNH patients persists during sleep. Those affected have been observed to not be able to voluntarily control their breathing in order to slow it down and the hyperventilation is predominantly controlled by the diaphragm.CNH has been found to affect people of all ages, ranging from children at the age of seven to adults at the age of eighty-seven. It has affected people while they have been both conscious and unconscious. After Plum and Swanson's initial discovery of CNH it was thought that CNH was rare in conscious patients. More cases of CNH have been observed in conscious patients since then. Additional symptoms of conscious CNH include loss of appetite, difficulty concentrating, poor memory, difficulties in eating or talking, cachexia
Cachexia
Cachexia or wasting syndrome is loss of weight, muscle atrophy, fatigue, weakness, and significant loss of appetite in someone who is not actively trying to lose weight...
, vomiting, disorientation, and a generalized confused state that varies from patient to patient. It is generally seen, however, that the mood changes, anxiety, and difficulty concentrating progress as the tumor increases in severity and, in effect, CNH persists. All of these symptoms are not present in each reported case of CNH, and symptoms seem to vary on a case to case basis. Other symptoms that have been associated with CNH are transient epileptic episodes with a temporary loss of consciousness. This condition is thought to result from severe hypocapnia that induces blood vessels in the brain to constrict, leading to brain ischemia
Ischemia
In medicine, ischemia is a restriction in blood supply, generally due to factors in the blood vessels, with resultant damage or dysfunction of tissue. It may also be spelled ischaemia or ischæmia...
. Other symptoms caused by CNH are electrolyte dysequilibrium and mood changes that primarily include anxiety due to the hyperventilation.
Once CNH is diagnosed, the condition generally progresses until the patient becomes unconscious or lapses into a coma. Most patients are seen to enter this state two to three months after the onset of CNH. Lange et al. cited a patient that experienced pulmonary edema, bronchitis, and pneumonia prior to death, though all reported cases of CNH describe various progressions of the condition until it worsens to the point of death.
Associations with Body Systems
CNH is most commonly associated with the central nervous system, and the majority of CNH cases have been associated with infiltrative tumors in the pons. Some cases involve the medulla and other regions of the brain. Primarily, researchers believe that the tumors infiltrate the pontine respiratory centers and central chemoreceptors. CNH has not been found to be associated with any other of the body’s systems. Cardiac, pulmonary, and metabolic disorders have been ruled out as causes of the hyperventilation. Tests such as electrocardiogramElectrocardiogram
Electrocardiography is a transthoracic interpretation of the electrical activity of the heart over a period of time, as detected by electrodes attached to the outer surface of the skin and recorded by a device external to the body...
s, echocardiograms, torso computed tomographic scans, and chest radiographs have revealed that the pulmonary and cardiac systems of CNH are normal. Liver and kidney functions are also normal. Lymph node and thyroid enlargement also have not been detected. Association with the cardiovascular system is seen when the brain tumors reach the medullary cardiovascular centers, at which point the patient usually succumbs to death.
Pathophysiology
Although CNH is typically characterized by the presence of lesions in the brainstem region, the mechanism by which these lesions create uninhibited stimulation of the expiratory and inhalatory centers is still poorly understood. These lesions typically arise after cancerous cells from another location of the body metastasize and move to the brain. The mechanism by which CNH was originally thought to occur involved the separation of the pontine and medullary respiratory centers by infiltrative tumors. Animal models mimicking this separation, however, do not exhibit CNH. A secondary postulated mechanism by which CNH may function is that the lesions produce lactate which consequently serves as a stimulator for the chemoreceptors of the medullary region of the brainstem. Previous studies of CNH patients have verified the presence of lactic acid in cerebral spinal fluid.Treatment
There is no accepted current course of treatment for CNH. Patients are usually supported by mechanical ventilationMechanical ventilation
In medicine, mechanical ventilation is a method to mechanically assist or replace spontaneous breathing. This may involve a machine called a ventilator or the breathing may be assisted by a physician, respiratory therapist or other suitable person compressing a bag or set of bellows...
and managed with paralytic agents to control breathing rate until a more specific treatment plan can be developed. Morphine
Morphine
Morphine is a potent opiate analgesic medication and is considered to be the prototypical opioid. It was first isolated in 1804 by Friedrich Sertürner, first distributed by same in 1817, and first commercially sold by Merck in 1827, which at the time was a single small chemists' shop. It was more...
is used as the most common treatment, specifically for its ability to depress respiratory rate by reducing tidal volume to added carbon dioxide. However, morphine has only been found to be effective in reducing CNH in select cases. Successful documentation of CNH treatment typically involves the surgical removal of the lesions, or the use of brain irradiation or chemotherapy with corticosteriods to reduce the size of lesions in the affected area of the brain. In cases where CNH presents in children, whose conditions are typically characterized by more solid tumors, aggressive surgical and chemotherapeutic methods are highly recommended.
If treatment of the lesions is ineffective, studies have shown that intravenous fentanyl, a slow-acting narcotic, or a fentanyl patch can be used to slow respiration. In patch form, fentanyl is a good alternative to morphine therapy for its high lipid solubility and ability to be worn on the body. Narcotic treatment is largely temporary and high morbidity rates in adults and children are typically cited where lesions are not effectively treated or removed.