The Cushing-Eisenhardt Brain Tumor Registry and the Neuropathology Collection

Dr. Harvey Cushing worked closely for many years with the neuropathologist Dr. Louise Eisenhardt, to establish and maintain a gross and microscopic brain collection that would supplement not only his clinical records and operative innovations, but would also continue to be developed as an educational resource.

By establishing the Hanna Fund for this registry in 1939, he also secured a funded permanent position for Louise Eisenhardt at Yale as its curator. This fund was designed to support the continuation of academic neuropathology at Yale, with the maintenance and ongoing replenishment of the collection as well as research. Dr. Elias Manuelidis became the curator of the Brain Tumor Registry when Louise Eisenhardt died in 1967, and in addition to the extensive written archives, slides, and many brain specimens stored in formalin, it included the beloved guppies of Dr. Eisenhart.

Dr. Elias Manuelidis promised Dr. Eisenhardt that they would be taken care of ad infinitum. The actual responsibility was assigned 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. The well-catalogued gross specimens of the original collection were kept in glass bottles in the Brady Basement of the Pathology Department, and had first been arranged there by Dr. Eisenhardt for viewing. This Brady pathology space was easily accessible, and bottles could be replenished with fresh formalin by the dieners, and viewed by many neurosurgical residents who trained under Dr. William German. Numerous additional precious brains for teaching were subsequently collected from the many autopsies done by the neuropathology team at YNNH, the VA, and at outside mental hospitals.

They were cataloged and arranged in this space, especially by Dr. Jean Angelo, whose handwriting is prominent on many carefully sealed bottles. This Brady viewing space was initially provided by Dr. Milton Winternitz, a legend of his own at Yale, and later graciously expanded by the Chairmen Drs. Harry Greene and Lewis Thomas. In fact, Dr. Greene did seminal work on malignant gliomas and other neoplasias with his assistant Betty Harvey, the daughter of Sam Harvey, and was a favorite teacher of many medical students (including LM).
All of Cushing’s written case records, along with Eisenhardt’s slide collection were housed in 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 Harvard neurosurgeons asked Dr. EE Manuelidis to give a talk and contribute a paper for the delightful celebration of Dr. Cushings 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 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. Unfortunately, during the translocation of Neuropathology to the Surgery Department, the Pathology Chairman 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 1979 the entire wet collection, including the original Cushing operative specimen, and the neuropathology tumor, dementia and rare disease collection was moved and organized 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. Although obscured, the Cushing wet collection was never “lost.” Drs. Collins (who just died in June 2009) as well as all the Neuropathology staff knew its location along with Dr. Harry Zimmerman, a neuropathologist, good friend and dedicated Yale Alumnus. In 1994 he proposed contributing to both the collection the neuropathology section at Yale. Unfortunately, his death in 1995 changed the course of his desire.
In 1996, the clinical neuropathology service component of Neuropathology was administratively moved back into the Pathology Department, and this precluded continuation of the approved Neuropathology residency program at Yale that had been in existence for ~40 years as well as the close interaction with many neurosurgery residents. 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.

The extensive slide, kodachrome and tissue block archives of Neuropathogy that were collected for over 40 years (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.
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 tumor could be rapidly and completely annihilated 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 CV) using new and archived specimens. These studies ultimately led to the realization of an inherent genetic variability in the more malignant gliomas see “Genomic stability and instability in different neuroepithelial tumors: A role for chromosome structure." The Neuropathology archive in the Surgery Department also maintains an extensive collection of dementia specimens, including many 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.
Many fundamental discoveries of their transmission were uncovered at yale, e.g., the demonstration that 1) the CJD infectious agent traveled to the brain via the bloodstream, 2) iatrogenic infections could derive from transplants, and 3) the CJD agent behaves as a viral particle with a protected nucleic acid genome. Please see the neuroscience page of LM at http://info.med.yale.edu/neurosci/faculty/manuelidis_main.html for further information on CJD research and viral particles, as well as in the banner above for the unique neuropathology of the “mad cow” variant of human CJD in mice and murine cultures. 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.