Clinical manifestations

Presentation and course

Due to the nature of the disease, no history can be gained from the patient. History can be obtained from alternative sources such as the family, cell phone, prescription bottles, environment in which the patient was found, and the physical exam. The clinical clues from the family members include the rate of onset. Vascular structural etiologies such as subarachnoid hemorrhage, intracerebral hemorrhage, and ischemic stroke have an abrupt onset. Toxicities and overdoses can have a slower onset over minutes. Classic physical exam findings can be found below (18):

Due to the nature of the presentation as an endpoint of many diseases and a clinical syndrome, the clinical variants are varied as listed below (09):

Prognosis and complications

Coma etiology strongly influences outcomes, with reported mortality ranging from 25% to 87% (05). Five percent to 25% of patients remained moderately-severely disabled or in a permanent vegetative state. The mortality was highest for stroke (60% to 95%) and postanoxic coma (54% to 89%) and lowest for poisoning (0% to 39%) and epilepsy (0% to 10%).

Clinical vignette

A 53-year-old woman with hypertension and diabetes, noncompliant with medications, and no history of migraines presented to the emergency room with her husband for confusion and increasing intensity of headaches. In the emergency room, she acutely became comatose with a Glasgow Coma Scale of 3 and no brainstem reflexes and was intubated with a systolic blood pressure of 220. She was transported to the CT scanner, where a noncontrast head CT revealed a cerebellar hemorrhage with edema and mass effect compressing the fourth ventricle with blood tracking into the pons and up into the midbrain. She then became hypotensive without intervention to systolic blood pressure of 90/40, requiring phenylephrine for stabilization. Neurosurgery evaluated the patient and found no brainstem reflexes. She was taken emergently to the operating room for decompressive craniectomy, clot retrieval, and frontal ventricular drain. She never regained consciousness or brainstem reflexes but was found to have SPECT uptake in the cerebral hemispheres and polymorphic delta on her EEG with normal transcranial Doppler waveforms. MRI revealed edema in the brainstem without infarction. Her family decided to proceed with tracheostomy with PEG tube and transfer her to a nursing home.

Biological basis

Constantin Von Economo wrote about encephalitis lethargica from 1917 to 1931 based on his experiences during World War I. He proposed that waking influence stems from the upper brainstem passing through the deep gray matter and that the sleep-promoting area is in the rostral hypothalamus. The rostral hypothalamic localization for deep sleep was subsequently confirmed by lesional studies on animals by Nauta, Sweett, and Hobson and Sterman and Clemente from 1939 to the 1960s (12).

Victims of Von Economo encephalitis lethargica were found to have lesions involving the paramedian reticular activating formation of the midbrain at the junction with the diencephalon. This suggested that circuitry causes arousal of the forebrain and was located in the brainstem (12).

The development of EEG in 1929 by Hans Berger revealed that the waveform patterns recorded decreased in amplitude and frequency in correlation to patients’ level of consciousness. In 1935, Frederic Bremer found that cats with transected spinal cords between the medulla and spinal cord had a desynchronized wakeful pattern, but transection between the superior and inferior colliculi caused a high voltage slow wave pattern indicative of deep sleep with clinical behavioral unresponsiveness (01). Subsequent experiments by Moruzzi and Magoun confirmed that the midbrain reticular core relayed arousal signals to the cortex. Further experiments in cats with transections from the midpontine level or below promoting a continuous wakeful state further supported the lower brainstem as a synchronizing or sleep-promoting area (10).

In the 1980s, it was found that the thalamus has relay neurons with burst and transmission modes of firing. The transmission mode firing was found to be mainly operating during wakefulness. Individual neurons fire in patterns that reflect their incoming afferent inputs, which correlate with a desynchronized EEG. Burst mode was found to be secondary to calcium-activated potassium current when sodium channels become hyperpolarized, leading to rhythmic bursts that correspond to the slow waves on EEG reflecting large amounts of synchronized excitatory inputs to the cortex. The synchrony was originally thought to be located in the thalamic reticular nucleus but has since been found to arise from mesopontine afferents that span the entire thalamus, mainly in the pedunculopontine and laterodorsal tegmental nuclei as well as the midline and interlaminar nuclei (07).

The mesopontine level in the brainstem contains at least three different monoamine groups that project through the hypothalamus to the cortex; the locus coeruleus projects through the paramedian midbrain reticular formation, and the lateral hypothalamus innervates the cortex diffusely (07). Serotonergic neurons in the dorsal and median raphe nuclei project through a similar course (07). Dopaminergic cells in an extension of the ventral tegmental dopamine group along the midline of the midbrain into the area around the cerebral aqueduct and through the paramedian midbrain reticular formation are most active in wakefulness (07). Lesions of the prelocus coeruleus and medial parabrachial nuclei have been found to produce profound coma.

There are also glutamatergic neurons thought to amplify the arousal signal in the mesopontine tegmentum that are incapable of maintaining a wakeful state in the absence of the other groups. As the ascending arousal systems pass through the hypothalamus, histaminergic neurons in the tuberomammillary nucleus and lateral hypothalamic area augment the ascending projections that project to the cortex and the thalamus (07). Some of the lateral hypothalamic neurons contain orexin or GABA and fire fastest during wakefulness (07). Cholinergic and noncholinergic neurons also augment the signal in the magnocellular basal forebrain nuclei receiving afferents from the hypothalamic and monoaminergic ascending systems (07).

Differential diagnosis

Differential diagnosis includes encephalopathy, locked-in syndrome, hypoactive delirium, catatonia, and psychogenic unresponsiveness.

Diagnostic workup

Diagnostic workup includes noncontrast head CT, first to differentiate structural versus nonstructural causes with consideration to CT angiogram head and neck to evaluation for basilar artery occlusion, then electrolytes, arterial blood gas, carboxyhemoglobin blood cultures in certain patients, hormones, and urine toxicology. If nothing is found, one should consider lumbar puncture for encephalitis and EEG for nonconvulsive status epilepticus.

Management

Diagnostic and therapeutic steps should occur simultaneously. An organized and sequential plan can form the basis for discovering common causes of unresponsiveness and for selecting studies for less common causes of coma (14).

Focused history and past medical history by collateral information should be reviewed first, then stat labs, head CT, and CTA head and neck for structural causes. If there is persisting uncertainty, consider EEG and lumbar puncture.