Drugs such as general anesthetics, which are addressed more fully in a later section, alcohol, opiates, barbiturates, antiepileptic drugs, antidepressants, and benzodiazepines induce coma by their direct effects on neuronal membranes in the cerebrum and RAS or on neurotransmitters and their receptors. Others, such as methyl alcohol and ethylene glycol, both act directly and by producing a metabolic acidosis. Although the coma of toxic and metabolic diseases usually evolves through stages of drowsiness, confusion, and stupor (and the reverse sequence occurs during emergence from coma), each disease imparts its own characteristic clinical features.
The sudden and excessive neuronal discharge that characterizes an epileptic seizure is another common mechanism of coma. Focal seizure activity has little effect on consciousness until it spreads from one side of the brain (and the body if there is a convulsion) to the other. Coma then ensues, presumably because the extension of the seizure discharge to deep central neuronal structures paralyzes their function. In other types of seizures, in which consciousness is interrupted from the very beginning, a diencephalic origin has been postulated (centrencephalic seizures of Penfield, as discussed in Chap. 15), but this idea has been contentious for decades.
Concussion exemplifies yet another pathophysiologic mechanism of coma. In closed head injury, it has been shown that at the moment of the concussive injury there is an transient but large increase in intracranial pressure, on the order of 200 to 700 lb/in2, lasting a few thousandths of a second. The vibration set up in the skull and transmitted to the brain was for many years thought to be the basis of the abrupt paralysis of nervous function that characterizes concussive head injury (commotio cerebri). While not excluding this mechanism, it is as likely that the sudden swirling motion of the brain induced by acceleration or deceleration from a blow to the head produces a rotation (torque) of the cerebral hemispheres around the axis of the upper brainstem. Disruption of the function of neurons in this region due to mechanical deformation is probably the proximate cause of loss of consciousness. These same physical forces, when extreme, cause multiple shearing lesions or hemorrhages in the diencephalon and upper brainstem. Chapter 34 fully discusses the subject of concussion.
Yet another unique form of coma is that produced by inhalation anesthetics. The effects of general anesthesia had for many years been attributed to changes in the physical chemistry of neuronal membranes. More recently, it has been recognized that interactions with ligand-gated ion channels, particularly gamma-aminobutyric acid (GABA)-A receptors and alterations in neurotransmitter function are a more likely mechanism of anesthesia-induced unconsciousness. An extensive summary of what is known about the metabolic neurochemistry of anesthetics has been given by Campagna and colleagues and by Brown and coworkers; it emphasizes the changes in neurotransmitter function rather than alterations in membrane fluidity but still do not give a unified theory of the effects of these agents, partly because different classes of drug act at different sites. Inhalation anesthetics are unusual among coma-producing drugs in respect to the sequence of inhibitory and excitatory effects that they produce at different concentrations. With anesthesia, sufficient inhibition of brainstem activity can be attained to eliminate the pupillary responses and the corneal reflexes. Both return to normal by the time the patient is able to speak. Sustained clonus, exaggerated tendon reflexes, and Babinski signs are common during the process of arousal. Rosenberg and associates systematically studied these findings. Preexisting focal cerebral deficits from strokes often worsen transiently with the administration of anesthetics, as is true to a lesser extent with other sedatives, metabolic encephalopathies, and hyperthermia.