Cerebral ocular Whipple's disease

In 1936, Drs. Frank R. Ford and Frank B. Walsh published a paper ^[1] entitled, "Clinical Observations upon the Importance of the Vestibular Reflexes in Ocular Movements". We will summarize one of the patients reported.

In January 1930, an otherwise healthy, 47-year-old man had onset of difficulty rotating his eyes upward. This was followed by difficulty with downward gaze. At night he had clonic movements of the left jaw. He then developed sexual impotence.

Neurologic examination on July 17, 1930, revealed only the absence of all vertical eye movements. The remainder of the neurologic and eye examinations were normal, as were the spinal fluid and skull x-rays. By October 1930, he had lost horizontal eye movements and was admitted to the Henry Phipps Psychiatry Clinic of the Johns Hopkins Hospital under the care of Adolph Meyer, the neuropsychiatrist, who was the first Professor of Psychiatry at Johns Hopkins Medical School.

On admission, the patient was described as having total inability to voluntarily turn the eyes in any direction. Clonic spasms of convergence, with the right eye turning in more than the left, were associated with clonic movements of the left face and jaw. Although inconstant, these movements could occur rhythmically at the rate of "about one per second". The pupils were normal. Visual acuity was diminished, and the corneas were hazy from superficial minute vesicles filled with clear fluid and circumscribed grayish-white patches in the deeper layers as seen by slit-lamp examination. Corneal sensation was decreased. No changes were seen in the optic fundi.

Passive head-movement maneuvers produced 15 degrees of up movement, smaller down movement, and full lateral movement of the eyes. Irrigation of each ear with cold water produced a "strong tonic deviation" to the same side, which lasted for 3 minutes without nystagmus. Rotation of the patient in a Barany chair produced a strong, persistent, tonic deviation to the side opposite the rotation, but no nystagmus.

The patient steadily worsened, vision deteriorated, bulbar palsies developed, and he died of pneumonia, 14 months after onset of symptoms. The report of Ford and Walsh ^[1] stated that there were widely scattered degenerative changes throughout the brain.

Summary of pathology--1931. We will review the final pathology report from Johns Hopkins Hospital, which provides more details than had been given in the report of Ford and Walsh ^[1].

At autopsy, the patient had an obliterative pericarditis and granular deposits on the mitral and aortic valves. Grossly, the brain sulci were widened, with some fluid and narrowing of the convolutions. There was marked destruction of the right cerebral peduncle and some shrinkage of the left peduncle (figure 1). Cut sections of the brain revealed marked atrophy of the convolutions. The upper part of the left putamen had a rough, granular, ragged appearance, with a pinkish color suggesting tumor rather than encephalomalacia. There was marked swelling of the basal ganglia and loss of normal architecture.

Microscopy of the brain showed a widespread encephalitis with focal necrosis almost exclusively in the gray matter of the cerebral cortex and corpora striata. Fat stains showed that, in some sections, every nerve cell contained numerous, rather coarse, varying-size granules and globules of fat. In other areas, many nerve cells were either necrotic or severely damaged. Some nerve cells looked swollen, with cytoplasm having a peculiar, very fine, granular, bluish-purple staining appearance. In some areas, neurophagocytes had fine, granular, bluish cytoplasm by hematoxylin and eosin (H-E) staining.

In an effort to distinguish this case from encephalitis lethargica, the observation was made that there were very few round inflammatory cells adjacent to blood vessels in the cerebral cortex. However, there was marked perivascular round-cell infiltration in the basal nuclei and pons.

The gross lesion of the putamen, microscopically, showed complete destruction with remaining nuclei containing the same fine, granular, pale cytoplasm described in other areas of the brain. The microscopist expected these cells to contain fat, but fat stains showed only pale, finely granular material.

The only ocular tissues reported in 1931 were the posterior segments. In the internal layers of the retina, many large, pale, granule-containing cells were seen and recognized by the pathologist as being similar to the cells in the brain. Anterior segment abnormalities, not described in the 1931 pathology report, were discovered by examination of slides retained in the pathology laboratory of the Wilmer Institute and are reported below.

Sections of the nodules of the heart valves revealed a few superficial clumps of hyaline material with a few leukocytes. The rest of the organs were relatively normal except for bronchopneumonia, from which grew a variety of organisms including a yeast. Histologic changes suggested "epidemic encephalitis".

1931-1966. Photographs and sections of the brain were stored in the neuropathology laboratory of the Phipps Clinic, where they remained for the next 35 years.

In June 1966, Dr. Simon Behrman, a London neurologist, was preparing an article ^[2] on supranuclear ophthalmoplegia. Behrman contacted David Knox and asked him to obtain the slides of Ford and Walsh's case for his review with Professor McMenemey, the neuropathologist at the National Hospital for Neurologic Disease, Queen Square.

Knox read the article and went to the still existing laboratory of Adolph Meyer, where Meyer's technician, Miss Cecelia Bisson, still worked, caring for Meyer's collection of pathologic material. Miss Bisson immediately brought to Knox the box containing slides from S.S.S., the patient reported by Ford and Walsh. She also displayed photographs (figure 1) she had taken of the gross brain and thick sections before histopathologic sections were made. She showed Knox the camera and mounting apparatus she had used, 35 years before, to take the photographs.

The slides were sent to England and returned 6 months later with a letter of thanks from Behrman. In their paper, Behrman and his colleagues described the details of the supranuclear ophthalmoplegia of Ford and Walsh's patient, but they did not comment on the pathology. Because Knox never throws anything away and because the department of psychiatry was then undergoing leadership and administrative turmoil, Knox kept the slides in his office. Meyer's laboratory was dismantled in 1970.

In the spring of 1993, Dr. David S. Zee began preparing for his Richardson Lecture at the University of Toronto ^[3]. His topic, "Adaptive Control of Eye Movements," led him to reread Ford and Walsh's 1936 paper. As a result of studies and papers by several investigators during the previous 20 years, the neuro-ophthalmologic community had come to realize that the combination of dementia, supranuclear gaze palsies, and myoclonus of face and other muscle groups was so strongly indicative of Whipple's disease that it was a first-exclusion diagnosis even in the absence of systemic manifestations.

After reading Ford and Walsh's paper, Zee called David Knox and suggested that the patient, with the initials, S.S.S., and the label, History # J 52789, was highly likely to have had Whipple's disease. Knox read the paper and agreed. He did not remember having read the paper before, and also failed to read the library card at the back of the volume, which would have told him he had read it on June 3, 1966. Knox's own experience with patients with Whipple's disease began in September 1966 ^[4].

Knox enlisted the help of John H. Yardley, ^[5,6] the gastrointestinal pathologist who had been one of the first to demonstrate, by electron microscopy, the presence of microorganisms in the tissue of patients with Whipple's disease. Yardley, using the "J" number, at first was told by Johns Hopkins' medical records personnel that a "J" number was not a valid number. Fortunately, an older worker remembered that J numbers had been used in the 1930s and found a record on microfiche. Yardley called Knox and asked if the name S S S meant anything to him. Knox, busy with a patient, replied, "not at the moment". Thirty minutes later, Knox's memory brought up the link. S S S was the name of the patient whose brain slides had resided in his office for 27 years.

Pathology, 1993-1994. Yardley's staff recovered both slides and blocks of paraffin-embedded tissue from remote storage. Coverslips were removed and brain tissue was stained with periodic acid-Schiff (PAS). Blocks were recut and microscopic sections stained with H-E, Luxol fast blue/PAS, and Bielschowsky's silver method and immunostained with antibodies for glial fibrillary acidic protein and neurofilament proteins.

Microscopic examination of the brain showed widespread inflammation throughout the cerebral hemispheres and brainstem; cerebellum was spared. Encephalitis was characterized by mononuclear cell perivascular cuffing and infiltration of white and gray matter, marked astrocytosis (figure 2A), and proliferation of microglia. The intensity of the encephalitis varied, being most severe in the striatum, where necrosis was noted at the center of a granulomatous lesion that contained abundant foamy macrophages filled with masses of coalescent PAS-staining granules (figure 2B). Similar accumulations were present in the cytoplasm of neurons, astrocytes, and perivascular inflammatory cells. Foci of PAS-staining material, admixed with reactive astrocytes, appeared as plaques and were widely distributed throughout the white and gray matter of the cerebrum.

Severe encephalitis involved the basal ganglia, thalamus, and hypothalamus. The posterior pituitary contained a few PAS-positive macrophages. Ependymal nodules, seen in the cerebral ventricles and aqueduct, stained positively with PAS (figure 3, A and B). In some of the aqueductal nodules, small discrete bodies were discernable on H-E stain. The columnae fornici, in the hypothalamus, medial to the optic tracts, appeared enhanced because of prominent glial proliferation and enhancement of septal bundles (figure 3, A and C). The architecture of the lateral geniculate bodies and pulvinar was markedly distorted by inflammation. Moderate inflammation involved the midbrain, tectum, posterior commissure, and periventricular gray matter, including those regions containing the rostral interstitial nucleus of Cajal. Pathologic changes in pons and medulla were mild. Leptomeninges showed minimal inflammatory changes. Spinal cord contained small PAS deposits in the gray matter.

Liver, spleen, pancreas, kidneys, adrenals, stomach, and intestines were all normal with no infiltration anywhere by macrophages typical of Whipple's disease, ie, multiple small, PAS-positive intracytoplasmic granules. The only exception, in a few portal areas of liver, was rare mononuclear cells that demonstrated PAS-positive cytoplasmic staining and did not consist of the granules characteristic of Whipple's disease. These cells were considered ordinary reactive macrophages, which can sometimes show PAS-positive staining. The acute bronchopneumonia was associated with a few PAS-positive rod-shaped bacteria that were presumably the causative agent. The slight valvular thickenings in the heart demonstrated only hypocellular hyaline scarring; no PAS-positive cells or other findings were present there or elsewhere in the heart.

Eye pathology. H-E-stained sections and paraffin blocks of ocular tissues were retrieved from the files of the Eye Pathology Laboratory. Examination of the original slides disclosed a few small clusters of large macrophages in the inner portion of the retina, especially around blood vessels, and moderate cystoid macular edema. Additional sections prepared from paraffin blocks disclosed numerous large clusters of macrophages with distended cytoplasm containing PAS-positive granular material in the inner portion of the retina (figure 4, A and B) and, to a lesser degree, in the cortical vitreous (figure 4C). Free bacilli, present in clusters and in a linear, Indian-file configuration (figure 5, A through D) were present in all nuclear and plexiform layers of the retina. The organisms stained well with the PAS reaction and did not stain with a tissue gram technique.

Anterior segment involvement included a fibrovascular pannus (figure 6A), protein in the anterior chamber, and distended macrophages in and along the anterior surface of the iris (figure 6B) and in the anterior chamber angle (figure 6C). The distal 10 mm of both optic nerves were free of involvement.

Electron microscopy. Examination of brain tissue taken from paraffin blocks was unsatisfactory because of autolysis.

The coverslip of one of the gelatin-embedded thick sections of cerebral cortex was removed, and the tissue was hydrated through a series of alcohols to water. The sections were fixed on a glass slide with 1% osmium tetroxide for 1 hour, after which they were rinsed with distilled water, dehydrated through a series of alcohols, and cleared with propylene oxide. The sections were infiltrated with a 50:50 mixture of resin and propylene oxide followed by a 100% solution of resin. The tissue was allowed to polymerize overnight in a 60 degrees C oven, after which it was separated from the glass slide. One-micron-thick and ultrathin sections were then obtained for light microscopy and electron microscopy. Examination disclosed large macrophages with numerous bacillary forms. Free bacteria were present (figure 7, A and B), and some were in apparent binary fission (figure 7C).

Examination of retina out of formalin and prepared for electron microscopy disclosed distended macrophages with numerous bacilli in varying stages of degeneration and numerous long free bacilli in the intercellular spaces (figure 8, A and B). The bacilli measured 1.5- to 3.0-microns in length and 200 nm in diameter. The bacilli were lined by a thin surface membrane and a thick (20 nm) cell wall. Occasional bacilli were undergoing binary fission (figure 8C). Some intact bacilli in an early stage of lysis displayed disorganization of cell walls. Other bacilli in later stages of degradation consisted only of inner cell wall layers that were arranged in stacks.

Discussion. In the 62 years from this patient's death to his diagnosis, three important evolutions in the understanding of the pathophysiology of Whipple's disease have occurred: (1) the role of infection, (2) CNS involvement that occurs in patients with and without systemic disease, and (3) the most common clinical features of the CNS disease. This patient's findings add to these evolutions.

Infection. The first evolution in understanding has been that Whipple's disease is an infection.

The concept that Whipple's disease was caused by microorganisms was proposed by Whipple himself ^[7] in 1907. He thought that small bodies stained by Levaditi's silver stain were microorganisms. His name, "intestinal lipodystrophy," as an explanation for the foamy, fat-filled intestinal and mesenteric lymph nodes obscured the concept of infection for 45 years.

In 1952, Paulley, ^[8] a British gastroenterologist, reported on a patient whose fever and elevated WBC count caused the patient's general practitioner to assume that this was an infection. The patient was cured by a course of oral chloramphenicol. In spite of this evidence, the concept of metabolic disease prevailed.

Simultaneously in 1961, Chears and Ashworth ^[9] and Yardley and Hendrix ^[5] presented electron microscopic evidence that many PAS-positive, foam-filled macrophages contained intact microorganisms. In 1969, de Groodt-Lassell and Martin demonstrated microorganisms in the brain by electron microscopy ^[10].

Multiple attempts have been made to culture the microorganisms in patients with Whipple's disease and, at this writing, studies by both Wilson et al ^[11] and Relman et al ^[12] are providing evidence that there are similarities in organisms from different patients. Koch's postulates, to establish that these organisms are the cause of Whipple's disease, have not been fulfilled. The difficulty in culturing these bacteria and their sometimes selective loci of tissue involvement suggest that they may have either an intrinsic parasitic nature or have acquired dependence on a human or other mammalian host. To our knowledge, no one has injected biopsy material from vitreous or brain directly into eye or brain of a laboratory animal as a method of culturing the organisms. At this time, no one has demonstrated or even postulated an origin or vector for these organisms. Cases have occurred in both geographic and family clusters ^[13]. Dobbins' ^[14] text summarizes the suggestions that these patients have an immune deficiency that prevents complete removal of microorganisms.

It is interesting to speculate what would have been learned if the pathologists in 1931 had stained the tissue with Levaditi's silver stain.

Central nervous system. Understanding of the involvement and pathology of the CNS in Whipple's disease has also evolved in the 62 years since this patient's death.

The PAS stain, developed by McManus in 1946, increased pathologists' awareness of the extensive systemic involvement in Whipple's disease ^[15,16]. Black-Schaffer ^[17] in 1949 first demonstrated PAS-positive material in both intestinal mucosa and mesenteric lymph nodes. Sieracki ^[18] in 1958 demonstrated PAS-positive material in axillary and inguinal lymph nodes of a patient with Whipple's disease.

Sieracki et al, ^[19] in 1960, were the first to present evidence of CNS involvement. They found PAS-positive material in ventricular ependymal nodules and in perivascular accumulations in two men, 35 and 59 years old. Lampert et al, ^[20] in 1962, presented the details of a 49-year-old man who died after 7 years of dementia and arthritis. His ependymal surfaces were studded with pinpoint, grayish nodules that contained PAS-positive material. Gray matter of the cortex and basal ganglia had microglial cells stuffed with PAS-positive material.

Badenoch et al, ^[21] in 1963, described a 48-year-old man with a known diagnosis of Whipple's disease affecting the gastrointestinal tract who then declined, with dementia, nystagmus, and fluctuating gaze pareses. PAS-positive material was found throughout the brain. Krucke and Stochdorph, ^[22] in 1962, presented a case with CNS Whipple's disease in which, for the first time, PAS-positive material was demonstrated in retina.

In 1977, Romanul et al ^[23] published the first report of a patient with Whipple's disease confined to the brain. This patient, at age 40 years, developed headaches and severe major motor seizures. Seven months later, he became confused and had severe headache. He had decreased attention span and poor memory. There were swollen optic disks with fresh hemorrhages. A brain biopsy found "granulomatous encephalitis". The patient progressively deteriorated and died 4 years after onset of his symptoms. At autopsy and by histopathologic study, including PAS stains, the brain was the only organ affected. Electron microscopy of cerebral lesions revealed characteristic microorganisms.

Three types of lesions were identified. The first had centers filled with PAS-positive cells in which bacterial ghost walls remained. The outer aspects of these lesions had intact organisms inside cells with PAS-positive material.

The second type of lesion had PAS-positive material and gram-positive organisms in microglial cells. The third type of lesion was a small scar representing an area that had healed because of the use of antibiotics.

These authors ^[23] thought that there was only cerebral involvement because the use of antibiotics in their case had cleared extracerebral tissues of microorganisms, also allowing complete phagocytosis of the PAS-positive material. They did not study the eyes. The original brain biopsy was studied and found to have PAS-positive material.

In a set of circumstances similar to ours, an autopsied patient, described in 1963 ^[24] as having an encephalitis, was diagnosed in 1979 ^[25] as having Whipple's disease because, in reviewing the material, J.J. Martin, a pathologist, became suspicious and stained the CNS tissue for PAS, which was positive. "Myorhythmies oculo-facio-cervicales" were the emphasized features of the first report ^[24].

Other cases of isolated CNS Whipple's disease were presented by Pollack et al ^[26] and Adams et al ^[27]. In 1991, Wroe et al ^[28] published a case with huge lesions demonstrated by MRI. In these there were rings of contrast enhancement, characteristic of infection, around the large areas of severe disease.

In 1978, Font et al ^[29] described the presence of bacteria, demonstrated by electron microscopy, in both the vitreous and retina of a patient who died of CNS Whipple's disease. Gartner ^[30] described a patient with CNS Whipple's disease, external ophthalmoplegia, and "severe asteroid hyalitis". Selsky et al ^[31] reported an ocular-only case, defined by electron microscopy, in a 70-year-man. Papilledema was present in a patient who also had PAS-positive material in optic nerve studied postmortem ^[32]. Sanders, ^[33] in 1975, presented the clinical details of a patient with papilledema and Whipple's disease.

The North American neuro-ophthalmologic community was first exposed to a patient with supranuclear ophthalmoplegia and myoclonic facial movements at the third meeting of the Neuro Ophthalmologic Pathology Symposium in 1971 ^[34]. (This yearly meeting later was named the Frank B. Walsh Neuro Ophthalmology Society.)

With recognition of CNS Whipple's disease, clinicians began to identify certain unique features of this disease. Supranuclear ophthalmoplegia has been prominent in many patients, some of whom have progressed to total ophthalmoplegia that did not respond to either head movement or caloric stimulation. Myoclonic movements of cranial musculature can occur independently or synchronously in eyes, jaws, or face ^[35-37]. Dementia is a prominent feature.

Implications of the present case. The most important aspect of the present case is that the patient had only CNS and ocular involvement from his Whipple's disease at a time prior to the development of antibiotics, which might have eradicated microorganisms in other tissues. From this evolves the speculation that there is something specific about the organism, or group of organisms, that in this and other cases has been demonstrated only in tissue of neuroepithelial origin. Organisms may have transiently resided in other tissues in this patient but, at death, there was no evidence that this had occurred.

While the neurologic involvement at the time of death was extensive, in the early phases of his disease, this patient's neurologic symptomatology and findings were similar to those of many other patients. It is difficult to understand how diffuse infection and cerebral involvement can cause such a specific abnormality as a supranuclear gaze palsy. Dementia and myoclonic contractions of facial and eye muscles are more easily understood on the basis of diffuse cerebral cortical disease.

Again, in this case, as in others, the use of the PAS stain helped in diagnosis and definition of tissues involved or spared. The stain had not been developed at the time of this patient's death in 1931. In other cases, the stain was not used at the time of brain biopsy or autopsy ^[23,24].

This is the second instance in which microorganisms have been demonstrated in the retina by electron microscopy. The report of Font et al ^[29] was the first. It is assumed in Krucke and Stochdorph's case ^[22] that the PAS-positive material in retina contained microorganisms. Other reports have described papilledema ^[23,32,33] for which there was no pathologic description. In the patient reported here, clinically described unique corneal lesions were confirmed pathologically. Other patients have been described as having "neuroparalytic keratitis". This is the first instance in which iritis is defined pathologically. Selsky et al ^[31] demonstrated PAS-positive material and bacteria from an aspiration of the anterior chamber.

This patient's neuropathologic findings, which are similar to those in other reports, begin with ependymal nodules that were most prominent in the aqueduct (figure 3, A and B) ^[19,21,23]. Astrocytic hyperplasia ^[24] and macrophage engorgement with abnormal material were described in other reports ^[21-27]. Diffuse inflammation and destruction is well established.

The unique finding in this patient's neuropathology is the diffuse thickening of the columnae fornicis, medially adjacent to the optic tracts (figure 3, A and C). This enlargement seems to be the result of microglial proliferation along the septae of these myelinated tracts.

Abnormal accumulations in the spinal cord have been reported only rarely ^[20,35]. In one report, PAS-positive material was seen in the pituitary stalk, as occurred in this patient's posterior pituitary. Large mass lesions, as seen in this patient's putamen, have been present in other patients ^[28,34].

This case demonstrates the value of the patient's hospital history number having been published with the original report ^[1] in 1936. It made it possible to find the record and pathologic material for current review, staining with PAS, and electron microscopy. The current practice of excluding any identifying information can be challenged by this case. Clinical investigators move, discard work sheets used in the preparation of papers, and die. Academia should develop sound, practical, libel-free methods for making identifying information available for later investigators.

Another aspect of this case worth emphasizing is the value of saving things even though one cannot be certain of when or whether they will be needed. The work of countless laboratory, medical records, and tissue storage personnel must be recognized. So much of what they do, they never see used. In this case, 62 years later, their work made a difference.

Another lesson from study of this case was the availability of the technology, electron microscopy, used to demonstrate microorganisms in tissue that had been fixed and mounted for 62 years.

This paper also honors two giants of clinical neuroscience, Drs. Frank R. Ford and Frank B. Walsh, who worked together for over 30 years. Ford, on the basis of a private practice and as an attending neurologist at Johns Hopkins, Baltimore City, and Rosewood State Hospitals, wrote the first text of pediatric neurology. When we knew him he had little hair but had told Walsh that as a young man he had had red hair and the associated violent temper. He realized that his displays of bad temper would prevent his developing a career in medicine, and he learned to control them. When Ford saw a patient as an inhospital consultant, he would arrive on the ward with his main neurologic equipment kept warm by his hat. For visual field testing, he kept a long, red-headed hatpin on the back side of the left lapel of his suit. He would read the chart, see the patient for a few minutes, do a few tests, and inform the patient that he would talk with the patient's doctor. Sometimes he wrote a short note. His comments were always laconic. At the end of his life he developed a fever of unknown origin which he explained by, "I am depressed". A ruptured appendix ended his life. His records were destroyed because he said that copies of his notes had been sent to the referring physicians.

Walsh, after service as a medical officer in World War I, practiced general medicine in Saskatchewan for 10 years before starting an ophthalmology residency at the Wilmer Institute in 1929. He began a clinical practice of neurodiagnostic ophthalmology in 1934 and had his first fellow, Thomas R. Hedges II, in 1948. Walsh hammered out many articles and the first two editions of his text Clinical Neuro Ophthalmology on an old typewriter. He co-authored the third edition with William F. Hoyt; the fourth edition is in the capable hands of Neil R. Miller. Walsh loved discussing interesting patients with any and all physicians. Story-telling was a part of his life. Near the end of his life he experienced formed visual hallucinations and commented that he must have cerebral metastasis from his small-cell carcinoma of the lung.

Ford and Walsh always addressed each other formally as "Doctor Walsh" and "Doctor Ford". They began clinical neuro-ophthalmology conferences in the mid-1930s in Baltimore, rotating them from hospital to hospital every 2 weeks until the 1940s, when they settled for 10:30 every Saturday morning at the Wilmer Institute of the Johns Hopkins Hospital. The conferences were attended by the leaders of the neurology and neurosurgery departments in the city, as well as house officers in neurology, neurosurgery, and ophthalmology. Walsh was the kindly master of ceremonies and Ford sat in the first seat of the front row, smoking or holding an unlit cigar behind his head. When the cigar twitched, we knew that either someone was making a fool of himself or that Ford wanted to emphasize a missed point in the case being discussed.

These clinicians learned and matured in the age of descriptive neurology. Their experience was vast, so they wrote and taught about what they had seen. We present this paper with the assurance that they would have exulted in the knowledge that a diagnosis and etiology were finally defined. In one sense, we continue to learn from them.