The Cushing-Eisenhardt Collaboration: Founding of the Brain Tumor Registry and Neuropathology Collection

Basic History

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Dr. Harvey Cushing worked closely for years with the neuropathologist Dr. Louise Eisenhardt, to establish and maintain a gross and microscopic brain collection. They wanted the collection as well as neuropathology to continue to be developed as an educational resource, and to include Cushing”s clinical records and operative innovations. Cushing thus established the Hanna Fund registry in 1939 and secured a funded permanent position at Yale for Louise Eisenhardt as its curator. This fund was designed to support  the future of academic neuropathology at Yale. Dr. Elias Manuelidis became the curator of the Brain Tumor Registry when Louise Eisenhardt died in 1967. In addition to the extensive written archives, slides, and many brain specimens stored in formalin, it included the beloved guppies of Dr. Eisenhardt. Dr. Elias Manuelidis promised Dr. Eisenhardt that they would be taken care of ad infinitum. The actual responsibility was assigned in 1966 to Dr. Laura Manuelidis, and the guppies faithfully generated with progressively duller colors for 20 years until one summer week, a generous neuropathology resident gave them too much food. Dr. Laura Manuelidis became head of the Fund and Registry in 1992.



The fragile wet brain specimens: In contrast to the guppies, the well-catalogued original gross specimens in addition to many new whole brain specimens collected from 1951-1977 were kept in glass bottles in the Brady Basement of the Pathology Department, as arranged by Dr. Eisenhardt for viewing in this accessible space. From 1951-1977 they were viewed by many students and neurosurgical residents who trained under Dr. William German and Dr. William Collins. The specimens kept in fresh formalin by the neuropathology staff along with other rare brain specimens such as Huntington’s Disease that were collected from other sites in CT. This Brady viewing space was initially provided by Dr. Milton Winternitz, a legend of his own at Yale, and later expanded by the Chairmen Drs. Harry Greene and Dr. Lewis Thomas. Dr. Jean Angelo’s handwriting is prominent on many carefully sealed bottles for the old and new specimen, and she maintained the wet specimens with a fastidiousness comparable to that of Dr. Louse Eisenhardt.

Pathology Department 1963:
Dr. EE Manuelidis, William McAllister, Harry Greene and Averill Liebow (front row, 4 at right)

The permanent (dry) collection: The extensive written records and slides were kept separately. These included all of Cushing’s written case records, along with Eisenhardt’s slide collection and were housed within the Neuropathology offices of Dr. EE Manuelidis, and maintained in perfect order by him. He took especial care not to permit this “dry” part of this archive to be depleted by the many neurosurgical residents rotating in Neuropathology who sometimes could not resist pocketing a small portable memento of Dr. Cushing.

The fame of the collection and its maintenance led the Harvard neurosurgeons to invite Dr. EE Manuelidis to give a talk and contribute a paper for the celebration of Dr. Cushing’s 100th anniversary (c.f., Manuelidis, E.E. "A neuropathologist's perspective on the celebration of the 2000th operation of Harvey Cushing." J Neurosurg 50(1): 13-16 (1979). The clinical and manuscript collections and slides of Cushing cases, the newer Neuropathology archives (~14,000 YNNH and VA slides and clinical cases from 1952 onwards), and the complete clinical service, training and research space in pathology became part of the Department of Surgery in 1979 when Neuropathology joined Neurosurgery under Dr. William Collins. The Brain Tumor Registry as well as the rest of the dry archives continued to be studied by many residents and trainees into the 1990s. Many students at Yale also looked at slides from the Cushing collection in the 1970s and 80s under supervision.

   

Transfer out of Pathology with loss of the wet specimen collection: During the move of Neuropathology to the Neurosurgery (Surgery Department), the Pathology Chairman unfortunately wanted all the wet Neuropathology teaching specimens removed from the Brady “museum,” as it was called by Dr. Eisenhardt. Despite protests from Drs. Collins, EE Manuelidis and L Manuelidis, in 1977 the entire wet collection, including the original Cushing operative wet specimens, and the neuropathology tumor, dementia and rare disease collection was moved in an organized fashion by Neuropathology to its newly designated space in the sub-basement of Harkness dormitory, a physically inaccessible location for replenishing and capping old jars, and impossible for teaching and viewing. It was considered by the Dean not be of any value and thus no funds were provided for its upkeep. Although obscured, the Cushing wet collection was never “lost” as claimed by the popular press. The students at Yale who had not know of its existence and stumbled on it where it was “rediscoverd” in ~1989. Drs. Collins (who died in June 2009) as well as all the Neuropathology staff knew its location along with Dr. Harry Zimmerman, a renown neuropathologist, good friend and dedicated Yale Alumnus. In 1994 he proposed contributing to both the collection the neuropathology section at Yale. His death in 1995 changed the course of his expressed wishes for his contribution to neuropathology.

At a neuropathology meeting: EE Manyelidis, Harry Zimmerman, Laura Manuelidis & Nick Gonatas.

Gift of Cushing and Eisehnardt clinical and case slides to Neurosurgery. In 1997, Neurosurgery became an independent department. Dr. Dennis Spencer then asked Dr. Laura Manuelidis if he might take Cushing’s collection to raise funds for easy viewing and upkeep at the Fulton house on Deepwood Drive. She agreed because she considered upkeep funds might be better generated by many neurosurgeons, particularly those who had studied the collection while at Yale. Plans were also proposed to embed some of the wet specimens in plastic by Dr. Spencer, and a medical student Chris Wahl was assigned to help with this project as his M.D. thesis. More about the subsequent funding can be found at http://cushingcenter.medicine.yale.edu/cc/journey


Pathology ~1970 Front row center: Levin Waters, Lewis Thomas, Haskill Milstone (LM above left of L Thomas)

Neuropathology: Non-Cushing Specimens

The extensive slide, kodachrome and tissue block archives of Neuropathogy that were collected for over 40 year (1952 to 1996) continues to be maintained. It is readily accessible in the Neuropathology offices with the corresponding written records. Many of these cases have been worked up beyond the standard diagnostic protocol with funds from grants for experimental work on human tumors and the Hanna fund. Numerous Yale papers have been written on the classification and biology of different brain tumors by the Neuropathology faculty and fellows, as well as by visitors in Neuropathology.

Tumor biology innovations: Dr. EE Manuelidis established the first human gliomas in tissue cultures from many of these samples. In a seminal paper with A. Pond in 1964 he showed that transplanted human malignant tumor could be rapidly and completely destroyed by intramuscular inoculation of a virus), "Oncolytic effect of poliomyelitis virus on human epidermoid carcinoma....” (PMID 14202523). Other experimental work on the biology of astrocytomas and glioblastomas underscored the effects of environment on tumor growth. An early interest in the potential genetic origin of environmental-induced changes led L. Manuelidis to discover some of the first human DNA sequences (alpha repeats and LINES, see major discoveries link) using new and archived specimens. These studies ultimately led to the uncovering the inherent genetic variability in the more malignant gliomas see “Genomic stability and instability in different neuroepithelial tumors: A role for chromosome structure."

Neuropathology Section: 1987 with contributors to fundamental work on Creutzfeldt-Jakob Disease (CJD)

The Neuropathology archive in the Surgery Department also maintains an extensive collection of dementia specimens, including many The Neuropathology rare and unusual human cases. It also was the first to establish faithful experimental models of human Creutzfeldt-Jacob Disease (CJD) in small rodents. These unique isolates or infectious agent strains of CJD have been propagated to a variety of settings. Several other human strains propagate here in normal rodents and tissue cultures include “mad cow” vCJD from UK residents and kuru from New Guinea (see major contributions CJD).

Many fundamental discoveries of their transmission were uncovered at Yale, e.g., the demonstration that 1) the CJD infectious agent travel by the blood to the brain, 2) inadvertent infections caused by transplants, and 3) the CJD agent behaves as a viral particle with a protected nucleic acid genome. We are happy to make the thousands of fastidiously catalogued experimental CJD slides and corresponding embedded brain and tissue specimens available for review and teaching.