A 65-year-old man presents with sudden onset of painless vision loss in his right eye for one day. He endorses subjective fever, decreased appetite, fatigue, mild headache, weight loss, and lower extremity numbness for two weeks.
He has a history of gout and benign prostatic hyperplasia, has a fever of 100 F, blood pressure of 140/90 mm Hg, and 98% on room air, and is a smoker. He is mildly uncomfortable. The patient has an afferent pupillary defect in his right eye, normal corneal inspection, full extraocular motions, and no photophobia. A funduscopic exam reveals central retinal vein occlusion in the right eye. Further exam reveals only hepatomegaly and decreased sensation in bilateral stocking distribution.
His lab values are a normal CBC, 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 apparent underlying diagnosis to explain all his symptoms, no pattern to be recognized, and no single laboratory test that secures the answer.
Where do we begin? The subjective symptoms are many, yet they are merely the brain's interpretation of the body's ailments. Because they are filtered through the mind of our patients, 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 the ailment speaking directly to us. To focus on the objective is to turn our attention away from what the patient is saying and toward what the body is doing.
The Most Vital Signs
As practitioners, we are essentially subservient to the vital signs. Fever, tachycardia, and tachypnea in this patient are signs of a systemic, possibly inflammatory, response.
The second sign is the afferent papillary defect (APD). It qualifies the subjective symptom of “vision loss” in 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, and mislead you into believing the problem is monocular rather than in the contralateral cerebral hemisphere.
Once you discover that the patient has an APD, 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. 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 or contralateral intracerebral disease alone because these would not explain the APD. The APD, not the symptoms of vision loss, now dictates your course of action.
A look at the fundus establishes the diagnosis of CRVO, without the need to entertain more specifics about the patient's symptoms, and without the need for a head CT.
Our patient has other objective abnormalities to be explained: hepatomegaly, extremity sensory loss, and abnormal creatinine and UA. For now, we will pursue only the systemic response and CRVO. We need a diagnosis that produces both. Let us begin with CRVO, which has a much narrower base.
Many cases are believed to be the product of an atherosclerotic central retinal artery pulsating and bulging into the central retinal vein. The result of this extrinsic compression is stasis within the vein and thrombosis. Although appealing, the local effects of chronic vascular disease would not explain his general discomfort on exam or his systemic response.
So we move on and ask, what are the principles of venous obstruction?
Endothelial damage: It may result from bacteremia and endotoxin production injuring vascular endothelium, producing secondary activation of the coagulation cascade diffusely (DIC). On this basis, we could obtain blood cultures, and start this patient on antibiotics. As for the immediate future, not much more can be done here.
Hypercoagulability: A number of derangements to the coagulation cascade can be responsible for CRVO. A large clot burden in the pulmonary circuit or an infected thrombus somewhere in the body would be necessary for the systemic response, though, and in this case, CRVO would represent a second thrombosed site.
Stasis: This is the most interesting. Extrinsic compression due to a retrobulbar mass within the orbit is unlikely given the absence of proptosis and lack of deficits to other cranial nerves in the orbital space. In that same sense, stasis from upstream obstruction, like cavernous sinus thrombosis, is also doubtful.
Climb into the vein: If not secondary to extrinsic factors, stasis may be a property intrinsic to the retinal vein and blood itself. A cellular element can result in increased viscosity, stasis, and thrombosis. But our CBC shows no such level of proliferation.
We are left with protein. An overproduction of one or more types of protein fueling hyperviscosity, CRVO, and a systemic response? Provided we are not injecting exogenous substances, all of the protein in blood can come from only one of two sources.
The hepatocyte. The trouble 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 and overproduce 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 could be characteristic of a hepatocyte irritated, tortured, or isolated by chronic infection, autoimmune irritation, or a fibrotic process; but not characteristic of the hepatocyte left to its own devices.
The B lymphocyte: I believe it to be more erratic, temperamental, and volatile than the hepatocyte. I submit that overproduction of protein to the extent of hyperviscosity would be more characteristic of a B lymphocyte than a hepatocyte, and we should be looking for immunoglobulin.
Innocent Until Proven Guilty
Presumption based on the nature of a cell is not enough. Fortunately, we have proof in the chemistry panel and the principle of electrical neutrality. 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 (AG), and must be in balance with the portion on the right. We all know the differential when the AG is large. But our patient has an AG=2. From the equation above, a low anion gap could be due to a drop in OA or a rise in OC.
The cleanest explanation for our narrow gap then would be an excess of cationic proteins. The predominant positively charged proteins are immunoglobulin, and to produce hyperviscosity, the component should be large. Dainty IgG monomers and IgA dimers are unlikely candidates. But the large IgM pentamer is a prime suspect.
Is the B lymphocyte responsible? It is likely not the sophisticated plasma cell. 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 is not the diagnosis here.
IgM seems to be the work of a less mature B cell. Proliferation of such cells we term Waldenström's macroglobulinemia. Hyperviscosity from IgM explains CRVO and hepatomegaly from stasis, intrinsic renal failure from glomerular debris, and a peripheral neuropathy due to congested vasoneurvorum.
The name is of little concern to me. Far more important is our understanding of the physiologic basis of disease and the personality of tissues and cells in building a unifying diagnosis. Can we look past the skin to see pathology course through the blood of our blind patient? If so, we may be able to recruit our consultant hematologist to initiate plasmapheresis quickly enough to save vision in his left eye.
About Diagnosis Deconstructed
Starting this month, Ravi Morchi, MD, will bring his considerable problem-solving skills to EMN in this new column. Dr. Morchi will take readers on an enlightening journey through the diagnostic process, from a thorough history to the final outcome, deciphering clues along the way, a true deconstruction of diagnoses using the art of medicine.