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Diagnosis Deconstructed: A Recipe for Encephalopathy

Morchi, Ravi MD

doi: 10.1097/01.EEM.0000470685.95089.2b
Diagnosis Deconstructed

Dr. Morchi is an associate professor of emergency medicine at UCLA's David Geffen School of Medicine. Read his past columns at http://bit.ly/MorchiCollection.

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Any organ failure can be broken down into pre-organ, intra-organ, and post-organ. Walking the circuit shows us our differential diagnosis. Not in a most emergent or most common listing, but in the order in which these entities truly reside within the body. In this way, the anatomic template provides us the opportunity to file our common and uncommon diagnoses in a retrievable manner.

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Pre-Brain

The approach to brain failure starts with carotid and vertebral artery flow. Is cardiac output low enough that cerebral perfusion is inadequate for normal mentation? If so, we need to pause here and deconstruct hypotension. When the MAP is reassuring, consider vertebrobasilar occlusion with reticular activating system ischemia. Provided the patient can comply, test cranial nerves and cerebellar function.

Move along the arterial lumen, and you enter microvasculature. Arteriolar narrowing in the chronically demented vasculopath is secondary to hypertension and diabetes. Retinal and glomerular sites can give us evidence of generalized insufficiency. Check the fundoscopic, creatinine, and urinalysis.

Acute microvascular occlusion is diffusely microembolic from valvular endocarditis or homegrown from luminal inflammation littered with microthrombi and PMNs in endothelial injury, bacteremia, DIC, or TTP. Occasionally, an immune process directed against endothelium will be the culprit. Type 2 or 3 hypersensitivity reactions can be filed here, including catastrophic antiphospholipid syndrome. Some of these patients will require plasma exchange, IVIG, or immune suppression. Rarely there will be an erythrocytic process like falciparum malaria or a hemoglobinopathy that clogs and injures cerebral capillaries and venules.

Thrombocytopenia at our antecubital blood draw may be our first clue to remote endothelial CNS dysfunction. Be aware of retina and glomeruli as representatives just as you would in the chronic state. But also look at the dermis. Skin findings can start macular, and then progress to petechia and purpura as inflamed capillaries rupture, sometimes mixed with small ischemic-appearing ulcerations of occluded arterioles. Encephalopathy of the dermal, retinal, or glomerular variety should raise our suspicion for a microvascular source.

Pause within small vessels to wade in blood and ask if one of its components can be the mediator of encephalopathy. Anemia? How about hyperviscosity from excess white cells, red cells, or platelets?

When cellular elements are normal on CBC, then survey plasma proteins. Albumin and fibrinogen are not usual suspects, so our focus should be on the immune globulin group. Bulky IgM pentamers cause hyperviscosity. Their positive charges can produce a narrow anion gap. Other Igs may orchestrate a direct attack against neuronal surface proteins. Such antibodies could have originated from an immune process initially aimed at an organism or neoplasm. The resultant confusion is termed a para-infectious or para-neoplastic encephalopathy (anti-NMDA receptor encephalitis being one example). If the infection has long since passed, the post-infectious encephalopathy could manifest along a spectrum similar to Sydenham's chorea or pediatric autoimmune neuropsychiatric disorders associated with streptococcal infections.

Hormones are plasma proteins that do not congest lumens or attack cell surfaces, but one should consider thyroxine and cortisol for their effects on neuronal behavior. Cytokines are another set of proteins that may mediate para-infectious or para-inflammatory encephalopathy from a distant source.

Smaller plasma components include glucose, protein waste (urea and ammonia), and sodium and calcium. Although routinely checked in confused clientele, these elements should be mentally filed in the plasma compartment as we run the circuit.

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Intra-brain

Penetrating arterioles pass the pia matter and are sealed from brain tissue by astrocyte foot processes that fuse around capillaries. This is the blood-brain barrier. Looking beyond that, we see neurons and astrocytes accompanied by ependymal cells, oligodendrocytes, and microglia. Any of these can overgrow, raising ICP and compressing the contralateral cerebral hemisphere or brainstem to produce confusion. Bleeding into the free spaces within this community of brain cells can do the same thing, sometimes presenting as encephalopathy.

When macrovascular, microvascular, blood components, and the neural neighborhood are not the source, then we must enter neurons. Neuronal inflammation is termed encephalitis or cerebritis, and can be bacterial, viral, or immune-mediated. Sampling the CSF can be diagnostic, whether or not associated meningitis is present.

Even if neurons are not inflamed, specific organelles can produce brain failure. Mitochondrial function is dependent on oxygen and glucose as a parent compound for the three carbon skeletons of the Kreb's cycle. In addition to hypoxia and hypoglycemia, mitochondrial damage is incurred by cyanide, carbon monoxide, other inorganic or organic toxin accumulation, and septic debris such as reactive oxygen species. Move away from the cell body and recognize that neuronal impairment can result from poor axonal transport or myelin breakdown. Either could have traumatic, toxic, or immune origins. If the cell body and axon are functioning properly, then travel to the distal point along an axon and survey neurotransmitter imbalances at the synapse. OTC medications, prescription medications, and legal and illegal drugs can alter GABA, acetylcholine, glutamate, norepinephrine, dopamine, serotonin, or histamine.

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Post-brain

When pre and intra-brain causes for failure are excluded, consider drainage. Dural sinus thrombosis or SVC syndrome can cause encephalopathy. As could an obstruction to the outlet for ventricular flow of CSF at the aqueduct or arachnoid granulations.

Replacing the standard EM grocery list differential with a recipe provides a flavor profile to our organ's failure and maps an anatomic route through which we encounter and understand the regular and rare diagnoses.

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