I know what you’re thinking: an amyloid angiopathic bleed, or perhaps a hypertensive bleed, in a patient with Alzheimer disease. That’s what I was thinking until I saw in the chart that abnormal white matter changes on MRI prompted the neurologist to order Notch3 genetic testing on the patient, which surprisingly came back positive for a mutation. The patient therefore carried a clinical diagnosis of Cerebral Autosomal Dominant Arteriopathy with Subcortical Infarcts and Leukoencephalopathy (CADASIL), despite the fact that she had no clear family history indicative of this disease and despite the advanced age of symptom onset. At autopsy, there was no evidence of amyloid angiopathy on Congo red stain. She did appear to have the PAS-positive vessel wall deposits that would be consistent with a diagnosis of CADASIL (see photomicrographs below). Plus, it is hard to refute a positive genetic test. The Notch3 test has excellent specificity, from what I hear. Also, I hear that there was some Korean study showing a relationship between CADASIL and brain hemorrhage. If anyone has any other ideas about what might be the diagnosis in this case, I would love to hear from you.

Click here to view the embedded video.

From the website:

The technique used in this table is already utilized suc­cessfully as a compliment to the conventional autopsy. Apart from avoiding cutting in the body the doctors can see things that are difficult to discover in a conventional autopsy. Furthermore, the technique opens up for new op­portunities in countries where autopsies are not accepted due to cultural reasons. The technique can also revolution­ize the traditional health care in many areas.

The intuitive way in which these images can be manipulated seems to me to add significantly to the usefulness of these scans. A multi-touch interface like this would be an interesting alternative for navigation of digitized slides.

Scientists have known for some time that HD is associated with a trinucleotide repeat mutation in the protein huntingtin on chromosome 4. But, since huntingtin is present throughout the brain, why does neurodegeneration in HD take place predominantly in the striatum (caudate and putamen)? Solomon H. Snyder and his team at Johns Hopkins University, in the June 5, 2009 issue of the journal Science, show that cytotoxicity in HD takes place because of the interaction of mutant huntingtin with a second protein, known as Rhes. It turns out that Rhes is a striatal specific protein, thus explaining the anatomic specificity of neurodegeneration in HD. Snyder and colleagues go on to show that cells in culture tend to sequester mutant huntingtin into an aggregate. But in the presence of Rhes, mutatant huntingtin cannot aggregate, suggesting that the soluble form of the bad protein is what causes damage.

An Associated Press article about the discovery posted on Forbes.com quotes Walter J. Koroshetz of NIH’s National Institute of Neurological Disorders and Stroke as follows regarding the implications of this new study: “The answers in one disease may have implications for another… There’s been people on both sides of the fence. This story plays to the role of the aggregates as not being the major problem but the soluble protein as being the major problem.”

Reference:
Subramaniam S, Sixt KM, Barrow R, Snyder SH. Rhes, a Striatal Specific Protein, Mediates Mutant-Huntingtin Cytotoxicity. Science 5 June 2009:
Vol. 324. no. 5932, pp. 1327 – 1330.

We looked at each other, my surviving sister and I, and said no. It wouldn’t bring her back. We had had enough. We wanted to get on with funeral plans. Another reason, I realized later, was a vague, underlying sense of distrust. We weren’t confident that the hospital could provide a thorough and competent autopsy, and even if it could, we didn’t trust the doctors to tell us the whole truth.

However, it does goes on to affirm the value of the procedure for alleviating relatives’ fellings of guilt after the death of a loved one, and provides some information about how to request an autopsy. It also points out that many of the real questions people have after the death of a loved one are deeper than those we patholgists are able to answer.

The Times is also featuring a “Consult” section in which two pathologists answer questions about autopsies. The comments are interesting reading.

Pathological Findings
Microscopic examination of the liver biopsy revealed approximately five small fragments of liver tissue. There was a mild portal infiltrate of mixed inflammatory cells without evidence of limiting plate inflammation. Within the lobules, there were scattered, randomly distributed foci of hepatocyte necrosis with mixed inflammation. In a few foci, collections of epithelioid cells suggestive of poorly-formed granulomas were seen. Only rare eosinophils were present. There was one large area of inflammation and fibrosis with central necrosis.

Diagnoses
Liver tissue with microabscess formation
Mycobacterial organisms present on special stains

Discussion
In an immunosupressed patient on numerous potent medications, the differential diagnosis of multifocal lobular necrotizing granulomatous inflammation is broad. The various causes of hepatic granulomas have different histological features that help to narrow the differential diagnosis. Sarcoidosis and primary biliary cirrhosis tend to favor the portal areas, while other causes do not typically display this pattern. In granulomas caused by tuberculosis, there is often caseating necrosis, while in cat scratch disease, tularemia, and Yersinia infection, granulomas frequently have a purulent center. “Fibrin-ring” granulomas comprised of a fat vacuole surrounded by a ring of fibrin, epithelioid cells, giant cells and neutrophils may be seen Q-fever, cytomegalovirus infection, toxoplasmosis, lupus, and a few other uncommon conditions. Finally, granulomas caused by drug toxicity are sometimes associated with an eosinophilic infiltrate.¹

In this case, a broad panel of special stains for bacterial, acid-fast, and fungal organisms was ordered. In addition, less common viral causes of hepatocellular necrosis, including cytomegalovirus, adenovirus, herpes simplex virus, and varicella-zoster virus, were ruled out by immunohistochemistry. A careful search of the entire biopsy at high magnification revealed only two acid-fast organisms. Interestingly, cultures obtained from this biopsy specimen at the time of presentation were negative (though a later urine culture grew Mycobacterium tuberculosis). Based on the biopsy identification of acid-fast organisms, the patient was treated for presumptive tuberculosis and has since done well.

1. Scheuer P, Lefkowitch J. Liver Biopsy Interpretation. 7^th ed. 2006. Elsevier.

Pathological Findings
At autopsy, no thymus tissue was present in the mediastinum. The great vessels were abnormal, with a vascular ring (right aortic arch with left ligamentum arteriosum ) encircling the trachea and esophagus. The lungs were extremely boggy and heavy with severe diffuse bilateral consolidation. There were no facial abnormalities.

Diagnoses
DiGeorge syndrome
Giant cell pneumonia

Discussion
DiGeorge syndrome is a congenital disorder characterized by abnormal development of the third and fourth pharyngeal pouches, which most notably give rise to the thymus and parathyroid glands. In most cases, DiGeorge syndrome, as well as the associated velocardiofacial syndrome, are associated with a hemizygous deletion of 22q11. Deletion of the TBX1 gene within this region is believed to be the principal defect leading to the disease phenotype.¹ A broad spectrum of abnormalities is seen in DiGeorge syndrome, but the triad of immune deficiency, cardiovascular abnormalities, and hypoparathyroidism constitute the classic syndrome. “Complete” DiGeorge syndrome refers to patients with athymia, defined as a profound decrease in the number of “thymic emigrants” (naive T-cells) in the blood. A subset of patients with so-called “atypical complete” DiGeorge Syndrome develops autoimmune phenomena (primarily rashes and lymphadenopathy) associated with oligoclonal T-cell proliferation, and presumably due to a lack of thymic T-cell education.² This patient’s profound immunosupression resulted in an overwhelming respiratory RSV infection.

In this clinical scenario, the differential diagnosis for the patient’s giant cell pneumonia is limited to viral infection. While the term “giant cell pneumonia” is usually reserved for cases due to measles, varicella-zoster, parainfluenza, and RSV infection may also result in the formation of multinucleated giant cells. The characteristic morphological feature of measles infection is eosinophilc intranuclear and intracytoplasmic inclusions. Varicella-zoster typically lacks intracytoplasmic inclusions, while RSV and parainfluenza lack intranuclear inclusions.³ In this case, immunohistochemical stains for RSV were strongly positive, and other viral stains were negative.

The typical histological findings in RSV infection are a combination of necrotizing bronchiolitis and interstitial pneumonia. Sloughed bronchial epithelium often fills bronchial lumina, and occasionally, diffuse alveolar damage and alveolar wall necrosis is seen. Giant cell pneumonia, as seen in this case, is a rare manifestation.³

1. Kobrynski LJ, Sullivan KE. Velocardiofacial syndrome, DiGeorge syndrome: the chromosome 22q11.2 deletion syndromes. Lancet. 2007 Oct 20;370(9596):1443-52.
2. Markert ML, Devlin BH, Alexieff MJ, Li J, McCarthy EA, Gupton SE, Chinn IK, Hale LP, Kepler TB, He M, Sarzotti M, Skinner MA, Rice HE, Hoehner JC. Review of 54 patients with complete DiGeorge anomaly enrolled in protocols for thymus transplantation: outcome of 44 consecutive transplants. Blood. 2007 May 15;109(10):4539-47. Epub 2007 Feb 6.
3. Katzenstein A, Askin F. Surgical Pathology of Non-neoplastic Lung Disease, 4th ed. (Major Problems in Pathology v. 13) Philadelphia: Elsevier 2006.

Pathological Findings
At autopsy, there was extensive supurrative mediastinal and hilar lymphadenitis, and both lungs were extremely boggy and heavy. Within the right upper and middle lobes, extensive areas of yellow-tan friable necrosis were present. The liver and spleen contained innumerable firm white-yellow punctate lesions in a miliary pattern, and there was a large right paratracheal abscess.

Diagnosis
Miliary tuberculosis with probable superimposed staphylococcal sepsis

Discussion
Miliary tuberculosis generally occurs when Mycobacterium tuberculosis organisms from a focus of infection in the lung travel through the pulmonary venous circulation and are disseminated through the systemic arterial system. The large necrotic focus in the right lung, as well as the miliary lesions in the spleen, liver, and lymph nodes were all shown to contain innumerable acid-fast bacilli. Pre-mortem sputum culture specimens contained rare acid-fast bacilli, and later grew M. tuberculosis. There was no known history of HIV infection at the time of presentation, but tests done shortly before death revealed that the patient was HIV-positive, with a high viral load. Given the patient’s presentation with leg pain and eventual sepsis, and his history of MRSA abscess, disseminated mycobacterial infection was not initially considered to be a likely diagnosis.

Macrophages are the primary cells infected in M. tuberculosis infection. The acid-fast organisms enter macrophages via receptor-mediated endocytosis. Via several mechanisms, the organisms block fusion of the phagosome and lysosome. In primary infection of an unsensitized person, the organisms replicate within pulmonary macrophages and alveolar spaces and are disseminated through the body for several weeks. Mycobacterial antigens drain to the lymph nodes, where T_h1 cells are presented with class II MHC proteins and IL-12 produced by antigen-preseting cells. The T_h1 cells secrete IFN-γ, which stimulates formation of the phagolysosome within the macrophage, as well as production of nitric oxide. After stimulation with IFN-γ, the macrophages secrete TNF, which recruits circulating monocytes to become the epithelioid histiocytes characteristic of the granulomatous response. In many people, this response stops disease progression without causing significant tissue damage. In others, the organisms continue to spread and the ongoing inflammatory response results significant tissue destruction. In this patient, the HIV-induced deficiency in CD4+ T-cell function likely resulted in inadequate stimulation of the macrophage bactericidal response, allowing unchecked replication of the organisms.¹

1. Kumar V, Abbas A, Fausto N. Robbins and Cotran Pathologic Basis of Disease, 7^th ed. 2007. Elsevier.