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A Visual Mystery Solved

Morchi, Ravi MD

Emergency Medicine News: April 2010 - Volume 32 - Issue 4 - p
doi: 10.1097/01.EEM.0000369262.69911.38
Harbor Pearls

Dr. Morchi is the director of the Medical Screening Examination program at Harbor UCLA Medical Center and an assistant professor of emergency medicine at UCLA's David Geffen School of Medicine.

A 65-year-old man presents to the ED with sudden onset of painless vision loss in his right eye that began the day before. He denies trauma. He endorses subjective fever, decreased appetite, fatigue, mild headache, lower extremity weakness, a 10 kg weight loss over two weeks, and easy bleeding at the gums after brushing his teeth.

Waldenstrom's macroglobulinemia shows congestion, hemorrhage, and leakage

Waldenstrom's macroglobulinemia shows congestion, hemorrhage, and leakage

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He has a history of gout and benign prostatic hyperplasia, is a smoker, has a fever of 100 F, blood pressure of 140/90 mm Hg, and 98% on room air. He is fatigued and mildly uncomfortable. The patient has an afferent pupillary defect in his right eye, but no photophobia in either eye. Otherwise, corneal inspection is normal, and he has full extraocular motions. A funduscopic exam reveals central retinal vein occlusion in the right eye.

Further exam reveals bilateral anterior cervical lymphadenopathy, hepatomegaly 4 cm below the costal margin, normal motor function other than 4/5 strength to ankle dorsiflexion and plantar flexion, and subjective decreased sensation in bilateral stocking distribution.

His lab values are a WBC of 6.8 × 103/mm3, Hgb 10 g/dL, PLT 88 × 103/mm3, Na 131 mEq/L, K 3.7 mEq/L, Cl 105 mEq/L, HCO3 24 mEq/L, BUN 18 mg/dL, Cr 2 mg/dL, GLC 140 mg/dL, and UA: 25 WBCs, 50 RBCs, 2+ protein.

This patient presents a problem. Although the proximate cause of his painless vision loss is clearly central retinal vein occlusion (CRVO), there is no immediately apparent underlying diagnosis to explain all his other symptoms and signs. There is no easy pattern to be recognized that would declare the source pathology, and no single laboratory test that secures the answer. In short, standard emergency medicine practice and reflex fail to provide a conclusion to his story.

Where do you begin? The problem is that the patient has an extended list of subjective symptoms, and he has an array of physical exam findings as well. Many would start with the chief complaint, and I cannot argue against that. In addition to trying to explain the chief subjective symptom, you also must try to explain the objective findings. All tangible, physical abnormalities require your closest attention. The subjective symptoms are many, yet in this patient (and all others) these are merely the patient's interpretation of his body's ailments. Because they are filtered through the mind and the mouth of a patient, subjective symptoms carry with them an inherent fallibility, prone to misinterpretation and error.

Objective findings on the other hand, are not dependent on a patient's interpretation. They are not the patient describing his version of ailment to you, but rather the ailment speaking directly to you. To focus on the objective is to turn your attention away from what the patient is saying and toward what the body is doing. Objective, tangible, physical abnormalities do not lie. They cannot be bargained with or reasoned against. They are there, and must be explained. They are direct manifestations of the underlying pathology, and may lead you to a diagnosis more rapidly than anything a patient says.

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The Power of the Objective

Consider a child presenting with left-sided abdominal pain. He or his parents may endorse that the pain is worse after eating and with coughing. They may claim that vomiting is a major component, but if the abdominal exam is entirely soft to deep palpation both during expiration and inspiration, you would question whether the patient really has an intraperitoneal problem. If instead, the child had nasal flaring, mild tachypnea, and rales at the left base, then you would order a chest x-ray expecting to find a basilar pneumonia.

The left lower lobe infiltrate should come as little surprise to you because the patient had objective signs of pulmonary disease: rales (indicating partially fluid-filled alveoli “popping” open during inspiration) and nasal flaring (a physiologic mechanism to entrain air in states of decreased pulmonary compliance). Both objective abnormalities are uncommon in abdominal pain of peritoneal origin. Intraperitoneal pathology may cut short inspiration due to peritoneal irritation as the diaphragm moves down and pushes abdominal contents out against the parietal peritoneum, but it does not decrease pulmonary compliance and would not necessitate nasal flaring.

Here the objective takes precedence over the subjective, and correctly leads you to the diagnosis in spite of the misinterpretation of symptoms by the patient or his family. This is one example of the power of signs over symptoms.

As in this month's case, pursuit of the overload of subjective symptoms would consume the patient's entire ED stay, and it may be more prudent to forego the symptoms and instead focus on the signs. Let the signs of disease determine your direction and your investigations.

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The Most Vital Signs

As in any case in medicine, the first objective signs that must be explained are the vital ones; they cannot be neglected. As practitioners, we are subservient to them. No patient should leave your care without your best attempt to explain their vital signs. Fever, tachycardia, and tachypnea in this patient may be signs of a systemic inflammatory response (SIRS). Whatever final diagnosis we reach, it should have within it the capacity to produce SIRS.

The second sign is the afferent papillary defect. This objective sign qualifies the subjective symptom of “vision loss” in both pathologic location and severity. That is, a patient complaining of vision loss in one eye may have blurry vision from a refractive error, a dark shade over one part or the entirety of his vision in the right eye, floaters, flashes of light, or any combination of these. What is more, the patient actually may be suffering from a right visual field cut (rather than a problem with his right eye), and could have misled you into believing the problem is monocular rather than in the contralateral cerebral hemisphere. The symptoms here can be misleading.

Once you discover that the patient has an afferent papillary defect, you know that light shined to the right retina either does not engage the right optic nerve or the optic nerve does not transfer the impulse to the third nerve nuclei in the dorsal midbrain, and it does not result in bilateral Edinger-Westphal nucleus activation and miosis. Following the clues of this objective sign, the differential diagnosis for his vision loss is rapidly narrowed down to only a few possibilities. Pathology within the vitreous impairing the path of light, diffuse retinal disease, a dysfunctional optic nerve, or pathology in the dorsal midbrain. He cannot have a refractive error alone or contralateral intracerebral disease alone because these would not explain the afferent papillary defect. The afferent papillary defect, not the symptoms of vision loss, now dictates your course of action.

A quick look at the fundus establishes the diagnosis of CRVO without any need to entertain more specifics about the patient's symptoms and without the need for a head CT, for that matter.

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In Pursuit

The patient has other objective abnormalities to be explained: hepatomegaly at 4 cm below the costal margin, 4/5 strength to ankle flexion, and a creatinine of 2 mg/dL with an active urinary sediment (indicative of intrinsic renal disease). But we should pursue only the vital signs and the CRVO for now. In combination, we would ideally like a diagnosis that causes both SIRS and CRVO. As for the former, there is a long list of underlying entities, the most pressing of which would be an infection (qualifying the patient as septic). So we'll focus on the second entity, which has a much narrower base.

The eyes are the window. If you were to read off the differential diagnosis of CRVO, you would find that hypertension and diabetes mellitus are two known causes. The reason? Many cases of CRVO are thought to be caused by a neighboring atherosclerotic central retinal artery pulsating and bulging into the central retinal vein. The result of this extrinsic compression is stasis within the vein that can result in thrombosis. Although appealing, the diagnosis of a static vasculopathy (atherosclerotic disease) in the central retinal artery is not sufficient for this patient because he clearly has SIRS, and is mildly uncomfortable on exam. Chronic vascular disease would not explain either of these findings.

Instead of moving down the list, we should step away from the list altogether and ask ourselves: What are the principles of venous obstruction? What produces venous obstruction in other parts of the body? We are very familiar with deep venous thrombosis in the lower extremities, and know that the principles of stasis, hypercoagulability, and endothelial damage promote vascular occlusion here. No doubt, the same processes could cause occlusion of the central retinal vein.

Endothelial damage. Unlike the femoral veins of the lower extremity, direct damage to the central retinal vein from trauma is unlikely because it is protected by the bony walls of the orbit. Endothelial damage may result from an intravascular cause. Bacteremia and endotoxin production could certainly injure vascular endothelium and result in secondary activation of the coagulation cascade diffusely. If extensive enough, this could result in clot burden within many blood vessels: disseminated intravascular coagulation. On this basis, some could argue we should obtain blood cultures, and start this patient on antibiotics. As for the immediate future, not much more can be done for this possibility.

Hypercoagulability. A host of derangements to the coagulation cascade (factor V Leiden, proteins C and S deficiency, antithrombin III pathology, etc.) can be responsible for CRVO and thrombosis elsewhere. It is not common for the hypercoagulability itself to produce SIRS directly, however. Some may say a large clot burden (especially in the pulmonary circuit) or an infected clot somewhere in the body may produce SIRS. In this case, CRVO would represent a second thrombosed site, but this is not the cleanest diagnosis.

Stasis. This is the most interesting. Stasis in the retinal vein from external compression due to an atheromatous central retinal artery is not sufficient to explain SIRS. Extrinsic compression from a retrobulbar mass within the orbit is also unlikely given that the patient has normal extraocular motions, no proptosis, and no other apparent defect to cranial nerves IV, V1, or VI (all of which run within a cramped orbital space). In that same sense, stasis from upstream obstruction, like cavernous sinus thrombosis, is also doubtful.

Climb into the vein. Could it be that stasis is not secondary to extrinsic factors, but rather a manifestation of factors intrinsic to the retinal vein, a manifestation of blood itself? Such a syndrome is termed hyperviscosity. A cellular element of the blood when overproduced can result in such an increase in blood viscosity that the resultant stasis and stagnation yields thrombosis. For larger cellular elements such as immature white blood cells in a lymphoblastic leukemia, one may only need a WBC value of 100,000 to produce hyperviscosity. For smaller elements like platelets, we may be looking at PLT counts of 1,000,000 µL or more before hypervisosity, stasis, and thrombosis ensue. But our CBC shows no such level of proliferation.

This begs the question, is there anything else in blood that can contribute to hyperviscosity? If not cellular, we are then left with the protein component of blood. If there were an overproduction of one or more types of protein to such an extent that the result is hyperviscosity, CRVO, and SIRS, then what would be responsible for producing it? Provided we are not injecting exogenous substances, all of the protein in blood can come from only one of two sources.

The hepatocyte must be a suspect. The trouble with this is that we instinctively know the hepatocyte to be one of the most loyal and hardworking cells in the human body. We do not expect it to shed its allegiance to the body and begin overproducing any single protein to the point that the entirety of vasculature becomes a stagnant, murky pool unable to deliver nutrients or siphon off cellular waste. Such behavior would not be characteristic of a hepatocyte.

We know that fibrosis may set in from years of alcohol consumption, segmentalizing bands of hepatocytes and cutting them off from communication with other small similar tribes. Some members of these isolated, imprisoned groups may go awry, and proliferate without regard to community standards. The result is cancer. Yet even when cirrhosis begets hepatocellular carcinoma in this way, we know that it is not the hepatocyte to blame, but rather the system that has imprisoned and secluded these tortured cells.

The same is true for the daily irritation the liver receives from certain chronic, uncontainable inflammatory processes. Such irritation continually prods the hepatocyte to overproduce a potpourri of protein. This protein eventually deposits in end organs like the myocardium and renal parenchyma. We term this as one specific type of amyloidosis. Again, the hepatocyte is not to blame. Society has failed to nourish it appropriately in both of these instances. The nature of the hepatocyte, left to its own devices, is one of loyalty and service.

Would anyone argue with the statement that the B lymphocyte is less loyal and less stable cell than the hepatocyte? I believe the B lymphocyte to be far more erratic, temperamental, and volatile than a hepatocyte. Indeed, many patients suffer from lymphoma or leukemia (some at very young ages) because of the lack of regard a B lymphocyte may have for the body that shelters it. I would hold that overproduction of a protein to the extent of hyperviscosity would be more characteristic of a B lymphocyte than a hepatocyte, and that we should be looking for immunoglobulins.

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Innocent Until Proven Guilty

But presumption based on the nature of a cell is not enough. Like the judicial system, we need some proof. Is there evidence? I would argue that we have indirect evidence pointing to the B lymphocyte. It comes from the chemistry panel and the principle of electrical neutrality. Consider this equation: cations = anions. Na + other cations (OC) = Cl + HCO3 + other anions(OA), or in short form, Na + OC = Cl + HCO3 + OA, or re-arranging, Na − (Cl + HCO3) = OA − OC.

The portion on the left is familiar to us as the anion gap. Generally 10-12, we all know the differential when it is large.

But what about our patient? His anion gap is 2 mEq/L. This is clearly low. From the derivation of the equation above, a low anion gap could be due to a drop in any anionic component of the blood or a rise in any cationic component of the blood. OA − OC = 2.

Because we are primarily concerned with an overproduction of protein, the cleanest explanation for our narrow gap would be if that protein had a positive charge. The predominant positively charged protein in the blood? Immunoglobulin. To produce hyperviscosity, the component should be large. So which Ig is responsible? The dainty and nimble monomer IgG and the dimer IgA are both unlikely candidates. But the large, bulky, IgM pentamer is a prime suspect. Which type of B lymphocyte would make IgM pentamer? It is likely not a plasma cell. Plasma cells are highly specialized and sophisticated. The aristocrats of B cell lineage, they would not stoop so low as to spend their days making a crude, unrefined antibody that rumbles clumsily through the vasculature. Their personality would not allow for it. So multiple myeloma (monoclonal proliferation of plasma cells) is not the diagnosis here.

IgM seems to be the work of a less mature B cell, a plasmacytoid cell. Proliferation of such cells is termed Waldenström's macroglobulinemia. Hyperviscosity from IgM explains all of the patients' signs: CRVO and hepatomegaly from stasis, intrinsic renal failure from glomerular vascular debris with excess protein and increased viscosity damaging the mouth of the nephron, and motor and sensory disturbances from a peripheral neuropathy. The longest peripheral nerves cannot be fed by the congested small blood vessels overlying their epineurium: congested vasa nervorum.

What is in a name? The name Waldenstrom's macroglobulinemia is of no concern to me. We as clinicians know the names of much pathology, but can we recognize the pathology when it is under our noses? Or are we better at wielding medical vocabulary than we are at navigating the human body? Can we reclaim the pathology when buried beneath scores of symptoms by focusing on the physical signs rather than being distracted by the subjective? Or are we shackled to memorization of protocol, mnemonic, and algorithm, left defenseless when these reflexes do not generate an answer.

And when whittled down to a few objective derangements that demand explanation, can we fall back on our understanding of the physiologic basis of disease and the personality of tissues and cells to build a unifying diagnosis? Can we look through the skin to see the disease course through the blood of our blind patient? If so, you may be able to recruit your consultant hematologist to initiate plasmapharesis quickly enough to save vision in his left eye.

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About Harbor Pearls

This column features interesting cases treated by the faculty and residents of the department of emergency medicine at Harbor-UCLA Medical Center. The department was established in 1978, its emergency medicine residency program one of the nation's first. The program has delivered care to the underserved communities of Los Angeles County for more than 30 years in a high-volume, high-acuity Level I trauma, pediatric trauma, critical care, and disaster resource center. Its mission is to deliver the highest level of care and promote a sense of service.

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