Dr. Raymond D. Adams: Last of the Giants

This month marks the publication of the ninth edition of the famed textbook Adams and Victor's Principles of Neurology, originally authored by Dr. Raymond D. Adams and his colleague, Dr. Maurice Victor. Dr. Adams, former chief of neurology at Massachusetts General Hospital and professor of neuropathology at Harvard Medical School, passed away on October 18, 2008 at Brigham and Women's Hospital of complications from congestive heart failure. He was 97 years old. Dr. Adams' contribution to both neurology and neuropathology was immeasurable.

(Pictured on the left at the Eunice Kennedy Shriver Center in Waltham, MA with Ms. Shriver, Sen. Ted Kennedy, and Dr. Malcom J. Farrell. Adams was the Shriver Center's first director. Source: Boston Globe 1970 file photo.)

Here's what some physicians have said about Dr. Adams' impact:

"A brain cutting was elevated to an art form in his presence and his ability to force us to think was an elegant legacy which he has left to all who studied with him."

Benjamin Rix Brooks, MD
Charlotte, North Carolina

Dr, Adams was "a pre-eminent neurologist and prominent neuropathologist as well, one of the greatest and last of the giants of both neurology and neuropathology back when they were hardly separate specialties."
Douglas C. Miller, MD, PhD
Columbia, Missouri

"Dr. Adams contributed greatly to the establishment of the E.K. Shriver Center in Waltham MA and he was instrumental in the education and training of many of us who were blessed to benefit from his knowledge of neurology and the understanding of persons with intellectual and developmental disabilities."

Jim Gleason, MD
Waltham, Massachusetts

"Ray Adams was one of the last of the pioneers and giants of both neurology and neuropathology, harkening back to the golden years of neuropathology when virtually all neuropathologists were neurologists. He integrated both in a way that is rarely seen in the 21st century. He and his kind will be tremendously missed."
John E. Donahue, MD
Providence, Rhode Island

"Dr. Adams' teaching had an enormous impact on the field of neurology, and all of us who worked with him came away from that experience thinking differently about our work."

Lee Vorderer, MD

Shriver Center
Waltham, Massachusetts

"What he did that really broke the field wide open is that he made maximum use of neuropathology to study diseases. He established neuropathology as the basic science of clinical neurology."
Allan Ropper, MD
Boston, Massachusetts

(Pictured with colleagues in 2002 at the Eunice Kennedy Shriver Center in Waltham, Massachusetts during the Raymond D. Adams Conference on Multiple Sclerosis.)

For more details on Dr. Adams' life, see this Boston Globe obituary.

Annual Meeting of Neuropathologists set for June 11-14 in San Antonio, Texas

If you go to the American Association of Neuropathologists website, you'll see the following on the homepage: "An annual meeting is held each year." Gee, if they held monthly meetings, I wonder how often those would be. Anyway... the 85th annual meeting of the association is being held June 11-14, 2009 at the Crowne Plaza Riverwalk Hotel in San Antonio, Texas. The Special Course, enigmatically titled Recent Advances that Impact Research and Clinical Practice, will feature College of American Pathologists president Jared Schwartz, MD, PhD (pictured). It should be an interesting meeting. I wish I could go; but due to other commitments I'll have to wait to attend the 2010 meeting in Philadelphia.

Best Post of January '09: Jett Travolta's fatal seizure unlikely related to Kawasaki's disease

The Jett Travolta Foundation has been set up to help kids with various impairments since I published the following post on January 11, 2009:

Everyone has heard about the tragic death of 16-year-old Jett Travolta (pictured with his dad, actor John Travolta) presumably as a result of a prolonged seizure. It's also public knowledge that Jett Travolta suffered from Kawasaki's disease. It's unclear that there was a connection between Kawasaki's disease and his seizure disorder. There's some evidence, however, that there may be a connection between seizures and Jett's possible autistic disorder. The Travoltas reportedly didn't acknowledge the possibility that Jett had autism, perhaps because their faith (Scientology) does not recognize autism as a legitimate entity. An autopsy is being performed, the results of which are unlikely to be released. But I doubt that an autopsy would shed light on any of these questions anyway. An autopsy may show an anatomic substrate for a seizure disorder (cortical heterotopia, hippocampal sclerosis, etc.), but pathologists will not be able to make a firm connection between the seizure problem and Kawasaki's disease. And there is no way an autopsy can confirm autism.

Formerly known as the mucocutaneous lymph node syndrome, Kawasaki's disease is an acute, febrile, multisystem vasculitic disease of children. The cause of Kawasaki disease is still unknown. It is currently the leading cause of acquired heart disease in children in the United States and Japan. Why heart disease? The coronary arteries get inflamed and compromise blood flow to the heart. (Source: Harrison's Principles of Medicine, 17th edition, 2008.) No mention is made in Harrison's textbook of Kawasaki's disease as a cause of seizure; nor have I ever heard of such a connection.

So, there are more questions than answers in this case; and I'm afraid that the pathologists involved will be of little help in answering these questions.

Thanks to my favorite Springfield, Illinois blogger, Marie of Disarranging Mine, for asking about this issue and prompting this post.

More on neurofibrillary tangles in teenagers

In a recent post, I presented a case of a teenager with neurofibrillary tangles. The tangles were present in cortex adjacent to meningioangiomatosis. Dr. Doug C. Miller wrote in that there are other circumstances in which you might see such tangles in a teen. He writes: "Other possibilities you might think about in a teenager with tangles (before you look at the slides): SSPE in which affected brain can have tangles; and gangliogliomas, as rare cases in which the tumor neurons may have tangles are described." Thanks, Doug!

What's the deal with the subcortical U-fibers?

FrontalCortex.com features lots of neuropathology, including podcasts from one of our favorite neuropathologists, Dr. Mark Cohen. In a podcast on demyelinating diseases, Dr. Cohen clarifies questions I've long harbored about the so-called subcortical U-fibers. The photomicrograph above (from the textbook Neuropathology by Ellison and Love) shows a blue myelin stain of an adrenoleukodystrophy case where the subcortical U-fibers are spared. The following is a transcription of Dr. Cohen's insightful comments on this topic. I should first clarify that when Dr. Cohen talks about the subcortical U-fibers being the "slowest myelinating fibers within the nervous system", he is not talking about conduction velocity, but rather about how long they take during one's lifetime to get completely myelinated. OK, here's Cohen:

"As you read through either your textbooks or the literature on leukodystrophies, you'll inevitably comes across a statement which describes either preservation, or lack of preservation, of the subcortical U-fibers. The subcortical U-fibers are, as the name implies, myelinated fibers just at the junction of the gray matter and the white matter which travel in a tangential, rather than radial, fashion connecting areas of cortex to other areas of cortex. What's special about these U-fibers, and why they are either spared or not in leukodystrophies, is that they comprise the slowest myelinating fibers within the nervous system. These U-fibers begin myelination early in gestation and often aren't completely myelinated until the third or fourth decade of life. Therefore, leukodystrophies in which the pathology is dependent on myelin turnover will demonstrate relative sparing of these fibers as the turnover is extremely slow; while in leukodystrophies which depend on toxic damage to the oligodendroglial cell, subcortical U-fibers are as vulnerable as other myelinated fibers within the nervous system."

Thank you, Dr. Cohen!

A teenager with tau-positive neurofibrillary tangles? What's going on?

Last week I wrote about the College of American Pathologist's neuropathology teaching cases. As an example of the kind of cases presented through this subscription, let me present to you photomicrographs from the most recent edition. Dr Roger McClendon from Duke (pictured above) provided a case wherein a teenager harbors cortical neurofibrillary tangles, vaguely evident in center of this H&E-stained slide:
The patient does not have Down's syndrome or any other reason to have Alzheimer's disease at this young age. And to prove that these are Alzheimer-like tangles, tau immunohistochemistry on the surgical specimen shows that these tangles are indeed tau-positive inclusions:
So? What's going on? See the comment to this post for the diagnosis and explanation.

The College of American Pathologists Neuropathology Eduction Program

I'm working through the College of American Pathologists Neuropathology Program with neurology resident Fazeel Siddiqui, MD. (who happens to be a contributor to Medinbytes.com, a resource for the Pakistani medical community). According to the CAP website, the Neuropathology Program "is designed as an educational program for anatomic pathologists, neuropathologists, and trainees to assess and improve their diagnostic skills and to learn of new developments in neuropathology. Each shipment contains a CD-ROM with eight cases that cover the spectrum of neoplastic and non-neoplastic disorders affecting the central and peripheral nervous systems, including infectious, degenerative, developmental, demyelinating, traumatic, toxic-metabolic, vascular, and neuromuscular diseases. Four of the eight cases in each shipment comprise a mini-symposium focused on a specific problem area in neuropathology. The other four cases cover a variety of nervous system diseases." The mini-symposium featured on the current CD-ROM focuses on new entities introduced in the 2007 edition of the World Health Organization Classification of Tumours of the Central Nervous System.

You get 4 AMA PRA Category 1 Continuing Medical Education Credits for answering and submitting the multiple choice questions associated with each CD-ROM. It should be noted that the images associated with each case are downloadable in PowerPoint format for use in your own lectures to medical students and residents. A one-year subscription to the program, which gets you two CD-ROMs (16 cases) , costs $346 for one subscriber (and $54 for each additional subscriber at an institution). Given the care with which these cases are selected and presented, the cost of the program is well worth the value!

Best Post of December '08: What's an 'atypical pituitary adenoma'?

Next up in our "Best of the Month" series is December, 2008's pick. This was an easy choice since, because it was the holiday season, there was only one post that month! Here it is:

We recently had a case at our institution of an atypical pituitary adenoma, confirmed by Bernd Scheithauer at the Mayo Clinic. What is implied by the designation of a pituitary adenoma as being “atypical”? Burger, Scheithauer, and Vogel -- in their textbook Surgical Pathology of the Nervous System and Its Coverings by (4^th Edition, 2002), page 469 – have the following to say on the matter: “In an effort to identify tumors likely to behave in an aggressive manner, a histologic category intermediate between ordinary or ‘typical’ adenomas and pituitary carcinoma has be established. The designation ‘atypical adenoma’ denotes tumors showing increased proliferative activity, that is, more than an occasional mitosis, an MIB-1 labeling index exceeding 3%, and p53 immunoreactivity. Because combinations of these findings are clearly associated with invasion and/or recurrence, the designation ‘atypical’ earmarks potentially more aggressive lesions. Its utility in identifying tumors capable of metastasis remains to be established in prospective studies.” In an associated photo caption, it is mentioned that nucleolar prominence is also a common feature of atypical pituitary adenoma.

Amaurotic Family Idiocy: A Brief History of Tay-Sachs Disease

I dusted off my copy of Pathology of the Nervous System (1921) by Drs. E. Farquhar Buzzard and J. Godwin Greenfield (both physicians at The National Hospital for the Paralyzed and Epileptic in London, UK) and came across this entry for Amaurotic Family Idiocy (Tay-Sachs Disease):

"This disease was first observed in 1881 by Warren Tay, who described fully the characteristic changes at the macula. Sachs, in 1887, investigated it from the neurological point of view and showed its familial character, as twenty-eight of his cases occurred in fifteen families. Since that time a large number of cases [have] been recorded, all of which have been the children of Jewish parents. Sachs called the disease 'amaurotic family idiocy,' but as the disease is not present at birth, but develops after the first few months, it is not properly classed as 'idiocy'."

In the nineteenth and early twentieth centuries, an idiot was defined as "a human being destitute of the ordinary intellectual powers, whether congenital, developmental, or accidental; commonly, a person without understanding from birth; a natural fool; a natural; an innocent." (Source: Webster's Revised Unabridged Dictionary from Dictionary.com website).

'Amaurosis', by the way, means 'blindness'.

Featured Neuropathologist: Jan E. Leestma, MD

Today I profile Dr. Jan Leestma, a prominent forensic neuropathologist. After a short biographical sketch, Dr. Leestma answers a few of my questions:

Born in 1938, Jan Leestma attended school in Holland before graduating from the University of Michigan School of Medicine in 1964. His anatomic pathology training was at University of Colorado Medical Center; and his neuropathology training was completed at the Albert Einstein College of Medicine in New York. After military service at the Armed Forces Institute of Pathology in Washington, DC, Leestma joined the faculty at Northwestern University Medical Center in Chicago. In 1985 he was at the University of Chicago for a couple of years, and then joined the Chicago Institute of Neurosurgery and Neuroresearch at Columbus Hospital in Chicago until 1999. Leestma was Assistant Medical Examiner and Neuropathology Consultant to the Cook County (IL) Medical Examiners Office from 1977 to 1987. Leestma retired from hosptial practice in 2001 and has focused on his private forensic neuropathology consulting practice since that time. Widely published, Dr. Leestma's most recent textbook is entitled Forensic Neuropathology (published in 2008 by CRC Press).

Jan Edward Leestma, MD (photographed in Malta in 2006)

Now let's put Dr. Leestma up on the witness stand and ask him a few questions:
What is the state of clinical neuropathology today?
Neuropathology is in the midst of change. Owing to the decline in hospital autopsies, the traditional practice of Neuropathology (once almost totally autopsy based) has moved to surgical neuropathology or research with little "service" responsibility. The field of Forensic Pathology has attracted a number of neuropathologists to seek training in that field and/or to contribute their knowledge to medical examiner's or coroner's offices, when once this was rare. Where the profession is going is unclear at least in the traditional or classical sense.

Are there major differences in the practice of neuropathology in the USA versus Europe and Asia?
Yes. In many other countries neuropathology has little or no status as it enjoys in the United States, but in others, namely in Europe, the profession is alive and well and providing valuable services in the traditional sense (autopsy and surgical neuropathology) in addition to research. Where once there were virtually no neuropathologists in China, it appears that there is a growing group who are actively publishing there now. Japan has always had some eminent neuropathologists who concentrated on that field exclusively, but there are many clinicians who have had training in neuropathology that actively contribute to the discipline and to the literature.

What should the neuropathologist consider before acting as an expert witness in a medicolegal case?
One must ask one's self if they can meaningfully and factually contribute information to assist the trier of fact (Judge or Jury) to render justice. They should be aware of the serious nature of potential testimony whether in a civil case of a criminal matter. Their testimony must be evidence based and derived from the methods and procedures of science, and not based upon beliefs, dogma, or pseudoscience. One must recognize, that at least in the United States, the legal system is adversarial and one must be able to withstand what this might mean. One must remember that one's testimony will be taken down verbatim and may become a public record, and that it may be recalled in any subsequent legal action and be subject to cross examination or criticism. One must always tell the "truth, the whole truth, and nothing but the truth". If one does these things, expert testimony, while rarely easy, can be professionally the right thing to do and can be fulfilling.

What training programs would you recommend to a pathology resident interested in doing a neuropathology fellowship?
This depends upon what one envisions for one's career. If one wants to do clinical neuropathology, one should seek out one of the large teaching institutions where traditional training programs still exist and which have a lot of clinical autopsy and surgical material from which to learn. The programs at the Massachusetts General and Brigham and Women's Hospitals in Boston come to mind, as do the programs at the University of Pennsylvania, Columbia University, Duke University, University of California, San Francisco and others like them. One might actually seek training at more than one institution, going to those that have special programs in molecular genetics of brain tumors, for example. If one envisions primarily a research career, the above institutions all have robust research programs, as do others. If there is an interest is forensics, one should plan on doing a forensic pathology fellowship also and to seek some education in biomechanics. If one plans to concentrate on a clinical specialty, such as Neurology or Neurosurgery one might not need a full residency in Pathology or Neuropathology, rather a more abbreviated program. Ultimately whatever program one follows, self-learning and scholarship will augment whatever a program might offer and provide a basis upon which one can rely.

Thanks very much to Dr. Leestma for sharing his biography and his perspective on clinical and forensic neuropathology with our readers.

Why does the herpes virus love the temporal lobes?

After my recent lecture on infections of the CNS, Southern Illinois University medical student Mike Sinha came up to the podium to ask why the herpes virus had a predilection for attacking the temporal lobes. I passed Mike's question on to Dr. Tom Smith, the neuropathologist who provided the photographs (see above) of herpes encephalitis for Robbins and Cotran Pathologic Basis of Disease (7^th edition). Dr. Smith wrote that the question is not completely resolved, but he directed me to a 2002 review article which addressed the issue (Journal of Neurology Neurosurgery and Psychiatry 2002;73:237-238). I quote from that article:

"Regarding the site specificity of herpes simplex encephalitis (HSE), the pathway of viral spread is probably more important than cell-type viral susceptibility. The unique anatomical localisation has been thought to result from entry of the virus via the olfactory pathway with spread along the base of the brain to the temporal lobes, a view that is supported by the immunocytochemical evidence of HSV antigens in the olfactory tract and cortex, as well as temporal lobes, hippocampus, amygdaloid nucleus, insula, and cingulate gyrus in patients dying from HSE. Another suggestion is that HSE may result from viral spread from the trigeminal ganglia to the temporal and frontal cortex, a view that is consistent with this known site of HSV latency."

Thanks to Mike Sinha for a provocative question and to Tom Smith for researching the response.