| Identifier |
932-1 |
| Title |
Supranuclear Paralysis of Up and Downgaze |
| Creator |
Shirley H. Wray, MD, PhD, FRCP |
| Contributors |
Tessa Hedley-Whyte, MD; David Zee, MD; Steve Smith, Videographer; Ray Balhorn, Video Compressionist |
| Affiliation |
(SHW) Professor of Neurology, Harvard Medical School; Director, Unit for Neurovisual Disorders, Massachusetts General Hospital; (THW) Massachusetts General Hospital, Boston, Massachusetts; (DZ) Johns Hopkins Hospital, Baltimore, Maryland |
| Subject |
Somnolence; Supranuclear Paralysis of Up and Downgaze; Vertical Gaze Palsy; Absent Convergence; Pendular Vergence Oscillations; Bilateral Lid Nystagmus; Tropheryma Whippelii - Infection; CNS Whipple's Disease; Supranuclear Paralysis of Up and Downgaze Infection - Whipple's Disease |
| History |
The patient is a 44 year old woman with a past history of ethanol abuse. She was transferred to the Massachusetts General Hospital (MGH) on 3/10/93 for evaluation of memory impairment, hypothalamic dysfunction and a one month history of diplopia and ataxia. In February 1992 (13 months PTA), she developed a rapid decline in short term memory, having problems recalling where she placed objects, what she had just eaten, or what she had just read. In June 1992 (9 months PTA), she experienced an episode of excruciating abdominal pain and hematuria. Investigation at an outside hospital included a negative IVP and CT of the abdomen. In September 1992, (6 months PTA), she was admitted to St. Mary's Hospital, Maine with increased confusion and decreased memory which prevented her working as a computer data entry clerk. Investigations included a normal brain MRI without Gadolinium, Cerebrospinal fluid (CSF): normal glucose, mildly elevated protein at 78 and l0 lymphocytes. An ESR 57 in 1 hr. An RPR test was reported positive, but a subsequent MHA-TP was negative. She had a serum Na of 123 and the syndrome of inappropriate ADH secretion (SIADH) was diagnosed and treated with fluid restriction. An EEG, thyroid function studies, liver function tests, chest CT, bronchoscopy, vitamin B12 levels, Lyme titers, and small bowel biopsy were within normal limits. An ANA was positive at 1:16, but the rheumatoid factor was <1:8. An iron deficiency anemia with low transferrin levels was diagnosed. Treatment with oral and IV thiamine was begun with some improvement in her confusion but little change in her impaired memory. In November 1992 (4 months PTA), she was admitted to Maine Medical Center. Her memory loss had progressed despite thiamine and her upgaze was impaired. A second lumbar puncture (post-thiamine) showed a normal protein and 2 lymphocytes. Several months PTA to MGH, she developed hypothalamic dysfunction with low levels of E2, FSH, LH and normal PRL levels. She had intermittent fevers of no discernible pattern up to 101.6 without rash or arthritis. Two months PTA, she had diplopia and three weeks PTA bilateral dry eyes and unsteady gait. On March 10, 1993, she was transferred to the MGH with a diagnosis of primary CNS vasculitis. Past Medical History: Formerly a heavy drinker i.e. a liter of rum/day, and routinely "getting hammered". 25 packs of cigarettes per year stopped 3 months PTA. Family History: Father died of presumed Alzheimer's disease, age 65. Mother died in her 60's from a stroke Patient, oldest of four children, brothers alive and well. On Examination: Slightly plethoric, disinhibited woman, afebrile, BP 120/70, pulse 92 regular. The salivary glands were palpable. The neck was supple with no lymphadenopathy. The chest, breasts, heart, abdomen and extremities were normal. Mental Status: Speech normal, no dysphasia. Disoriented in time and place. Memory recall 0/3 objects after 3 minutes. Unable to subtract 3 from 100. Neuro-ophthalmology examination: Visual acuity 20/30 OU. Fundus examination normal discs and fundi OU. Pupils 3 mm OU, sluggishly reactive. Light-near dissociation was not present. Pendular vergence oscillation in primary gaze. Absent vertical, saccadic and pursuit movements both up and down with preserved vestibular ocular reflex. Absent convergence Full horizontal gaze to the right and left. No abnormal movements of the face or limbs. Neurological examination: Cranial Nerves intact. Sensory nervous system normal. Motor system: Normal, no ataxia Reflexes: UE reflexes symmetric 1/4, LE reflexes 2/4, knees and 1/4 ankles, plantar responses: flexor bilaterally. Hematological studies: NA 138, K 4, Cl 105, CO2 29.8, BUN 15, creatinine 0.8 WBC 10.1, Hct 36.2, platlets 397K Alk phos 90, SGOT 18, CK 42 PT 9.7 (10.3 control), PTT 23.4 Porphyria screen negative Vitamin B12 level 547. EKG normal. Brain MRI: Demonstrated an area of T1 brightness in the hypothalamus, including the mammillary bodies and the anterior hypothalamus, as well as "small vessel changes" in the pons of uncertain significance. MRI with Gadolinium demonstrated a marked enhancement of the hypothalamus. In addition the infundibulum (pituitary stalk) was seen to enhance abnormally, although it was not thickened or otherwise distorted. A follow-up MRI on June 8, 1993 was notable for a relative increase of enhancement within the hypothalamus compared to the previous study. In addition, the abnormal signal within the pons was appreciated more clearly and there was a possible abnormal signal surrounding the midbrain aqueduct. Lumbar puncture: Opening pressure 18 cm. H20, glucose 55 mg/dl, protein 45 mg/dl, RBC's 213, WBC's 8, 92% lymphocytes and 8% monocytes. IgG 3.5 (0-8.6), albumin 20.8 (11-48), oligoclonal bands absent. A second LP 2 weeks later showed protein 50 mg/dl, glucose 66 mg/dl, 4 WBC's, negative for PAS. CSF cytology negative. Rheumatology Studies: ESR elevated 80 mm. in l hr. Very high level (443 units) of anti-neurophil cytoplasm antibody (ANCA) with an atypical nuclear pattern of staining. ELISA confirms the presence of antibodies to myeloperoxidase - a finding of unknown significance. ANA, anti-Ro, anti-La negative. Angiotensin converting enzyme 22.8 (10-50). Anticardiolipin antibodies slightly elevated: IgG 24.8 (0-23), IgM 13.4 (0-11). A Russell Viper Venom test was negative. Cryoglobulins positive with slight cryoprotein with homogeneous IgM kappa. Serum protein electrophoresis abnormal IgM arc with elevated IgM 560 (56-352), IgA 479 (70-312), and negative urine Bence-Jones. Infectious Disease Studies: PPD negative, mumps positive. HBSAG, Hepatitis C Ab, CryptoAg, HIV, Brucella, tularemia, heterophile serologies negative. An RPR was positive at 1:8, but an MHS-TP was negative. CSF meningoencephalitis screen was negative. Malignancy Studies: Chest CT, cervical biopsy, CA-125 levels, mammogram and abdominal CT all negative. Pelvic ultrasound revealed a physiologic R ovarian cyst. Renal Studies: Urinalysis revealed 5-10 RBC. Therapy: An empiric course of high dose intravenous methylprednisolone (1 g IV q.d. x 3D, 500 mg x 3D, 250 mg x 3D) produced a transient improvement in extraocular movements, memory and hypothalamic enhancement as seen on MRI. However, by the end of the 9 day course, she became worse. Cyclophosphamide 100 mg p.o. q.d. was begun along with prednisolone 25 mg p.o., q.d. with possibly some transient improvement in memory. Her treatment was complicated by a sodium level of 118 secondary to increased fluids required for kidney protection during cyclophosphamide therapy. The regimen was changed to q month IV cyclophosphamide pulses with 25 mg p.o. prednisone. The NA level remained under better control on this regimen. The ANCA level progressively decreased from 443 (3/20) to 262 (5/10) to 61 (5/17). Despite this regimen, the MRI showed increased enhancement and T2 brightness of the hypothalamic lesions seen on MRI on 6/13/93 and 7/13/93, and lesions in the pons, and midbrain raising the question of possible CNS lymphoma. Procedures: Renal biopsy negative except for thin basement membrane syndrome. Lacrimal gland biopsy performed on 3/16/93 for dry eyes and palpable salivary glands was negative. Random brain biopsy (frontal lobe) normal. An open brain biopsy of the hypothalamus, performed on 8/25/93 showed perivascular and parenchymal infiltration with foamy macrophages laden with periodic acid Schiff positive material consistent with a diagnosis of Whipple's disease due to the bacillus Tropheryma whippelii (T whippelii). Unfortunately, neither electromicroscopy or the polymerase chain reaction (PCR) could be performed satisfactorily on CNS tissue to confirm the diagnosis. Subsequently re-evaluation of the jejunal biopsy, which had been obtained during her admission to St. Mary's Hospital, was confirmatory. Treatment: She was treated with two weeks of IV penicillin (following PCN desensitization) and IM streptomycin and started on a course of intravenous trimethoprim/sulfamethoxazole for two weeks followed by oral trimethoprim/sulfamethoxazole twice daily for one year. She was discharged (12/16/93) ten months after admission to a chronic nursing facility. Follow-Up: Reexamination six months later showed recovery of vertical upgaze, limited downgaze and absent convergence. Horizontal gaze was full with gaze evoked nystagmus. The severity of her dementia was unchanged. MRI eight months later (10/7/93) revealed decreased T2 signal in the pontine and medullary lesions and possibly increased T2 in the hypothalamus. |
| Anatomy |
Massive infiltration of infected tissue by macrophages typifies Whipple's disease. The bacillus Tropheryma whippelii multiplies in both monocytes and macrophages in Whipple's disease. The inflammatory reaction in the brain has a predilection for the periaqueductal gray matter, the hypothalamus and the hippocampus, and also the cerebral cortex, basal ganglia and cerebellum. The classic tool for diagnosing Whipple's disease is periodic acid Schiff (PAS) staining of small-bowel biopsy specimens, which on light microscopical examination show magenta-stained inclusions within the macrophages of the lamina propria. (Figure 1). Several biopsy samples should be studied, because the lesions are often focal and sparse. Immunohistochemical staining with polyclonal rabbit anti-T Ripley antibody has been used to detect the organism in various tissues, and bodily fluids such as the aqueous humor and on blood monocytes, providing direct visualization of the bacilli. Polymerase chain-reaction (PCR) assays can be used to detect T-whippelii. The bacterial 16S ribosomal RNA sequence can be amplified directly from a variety of tissue(s) and body fluids including CSF, first with broad-range primers and then with specific primers. Now, on the basis of genome analysis, a new quantitative real-time PCR assay has been developed that targets repeated sequences of T-whippelii with substantially greater sensitivity than the earlier PCR assays and the same specificity. As with all PCR assays, it is critical to avoid contamination of the DNA sample and to include positive and negative controls to validate the test. It is important to pay attention to a positive PCR assay even when a duodenal biopsy specimen is negative on PAS staining. |
| Pathology |
Described above |
| Disease/Diagnosis |
CNS Whipple's Disease. |
| Clinical |
This patient with Whipple's disease shows: • Constant pendular vergence oscillations (PVOs) in primary gaze • Absent vertical saccadic and pursuit eye movements up and downgaze • Preservation of oculocephalic reflex. • Convergence absent • The pupils showed no light-near dissociation • Optokinetic testing no convergence retraction nystagmus. The second clip, six months after discharge, and while still on therapy shows: • A marked Cushionoid appearance • Vertical upgaze has almost fully recovered. • Vertical downgaze still impaired • Convergence absent • No PVOs or nystagmus. She had persistent: 1. Loss of memory and was unable to recall having seen the examiner before 2. Impaired orientation 3. Severe cognitive dysfunction. Comment: PVOs are characterized by: • Smooth, pendular, divergent movements occurring at a frequency typically about 1 Hz. • Oscillations continue under closed lids and during sleep • Oscillations usually accompanied by a supranuclear paralysis of vertical gaze initially suggestive of progressive supranuclear palsy. Conclusions from the analysis of eye movement recordings in a patient with and Whipple's disease and oculomasticatory myorhythmia (ID42-1). 1. PVOs are smooth rather than saccadic and have the velocity characteristics of normal convergence and divergence eye movements. Despite the absence of other components of the near triad (miosis and accommodation), the disorder retains certain features characteristic of normal vergence movements. 2. The eye movements are disjunctive, and furthermore the peak velocities achieved for various amplitudes are typical of normal vergence movements. 3. The pathological alterations resulting in PVO implicate a separately functioning, physiologically normal vergence system within the brainstem. 4. The continuous nature of PVOs distinguishes them from the nystagmus that occurs with Parinaud's syndrome, which is episodic and provoked by voluntary saccadic eye movements, especially attempted upgaze. 5. In cerebral Whipple's disease the abnormal eye movements have been ascribed to oscillations of the vergence system; hence the term pendular vergence oscillations. PVOs may represent a definitive neuro-ophthalmic sign of Whipple's Disease. (Schwartz MA, Selhorst JB, Ochs AL, Beck RW, Campbell WW, Kim Harris J, Waters B, Velasco ME. Oculomasticatory myorhythmia: A unique movement disorder occurring in Whipple's Disease. Ann Neurol 1986;20:677-683.) |
| Presenting Symptom |
Confusion, memory loss and mild dementia |
| Ocular Movements |
Supranuclear Paralysis of Up and Downgaze; Absent convergence; Pendular vergence oscillations; Bilateral lid nystagmus |
| Neuroimaging |
Described above |
| Treatment |
The standard for antibiotic therapy currently favors antibiotics that are capable of crossing the blood-brain barrier, such as trimethoprim-sulfamethoxazole. This therapy is usually preceded by parental administration of streptomycin together with penicillin G or ceftriaxone for two weeks. For further details see Fenollar et al Whipple's Disease N Eng J Medicine 2007;3566:55-66. |
| Etiology |
Tropheryma whippelii infection |
| Supplementary Materials |
Whipple's Disease: https://collections.lib.utah.edu/details?id=2174246 Pendular Vertical Oscillations: https://collections.lib.utah.edu/details?id=2174230 |
| Date |
1995 |
| References |
1. Averbuch-Heller L, Zivotofsky AZ, Remler BF, Das VE, Dell'Osso LF, Leigh RJ. Convergent-divergent pendular nystagmus: Possible role of the vergence system. Neurology 1995;45:509-515. http://www.ncbi.nlm.nih.gov/pubmed/7898707 2. Fenollar F, Puéchal X, Raoult D. Whipple's Disease. N Eng J Medicine 2007;356:55-66. http://www.ncbi.nlm.nih.gov/pubmed/17202456 3. Gerard A, Sarrot-Reynauld F, Liozon E, Cathebras P, Besson G, Robin C, Vighetto A, Mosnier JF, Durieu I, Vital Durand D, Rousset H. Neurologic presentation of Whipple disease: report of 12 cases and review of the literature. Medicine 2002;81:443-457. http://www.ncbi.nlm.nih.gov/pubmed/12441901 4. Knox DL, Green WR, Troncoso JC, Yardley JH, Hsu J, Zee DS. Cerebral ocular Whipple's disease: A 62-year odyssey from death to diagnosis. Neurology 1995;45:617-625. http://www.ncbi.nlm.nih.gov/pubmed/7536902 5. Relman DA, Schmidt TM, MacDermott RP, Falkow S. Identification of the uncultured bacillus of Whipple's Disease. N Eng J Medicine 1992;327:293-301. http://www.ncbi.nlm.nih.gov/pubmed/1377787 6. Warren JD, Schott JM, Fox NC, Thom M, Revesz T, Holton JL, Scaravilli F, Thomas DG, Plant GT, Rudge P, Rossor MN. Brain biopsy in dementia. Brain 2005;128:2016-2025. http://www.ncbi.nlm.nih.gov/pubmed/15901648 7. Whipple GH. A hitherto undescribed disease characterized anatomically by deposits of fat and fatty acids in the intestinal mesenteric lymphatic tissues. Bull. Johns Hopkins Hospital 1907;128:382-391. |
| Language |
eng |
| Format |
video/mp4 |
| Type |
Image/MovingImage |
| Source |
3/4" Umatic master videotape |
| Relation is Part of |
42-1 |
| Collection |
Neuro-Ophthalmology Virtual Education Library - Shirley H. Wray Neuro-Ophthalmology Collection: https://novel.utah.edu/Wray/ |
| Publisher |
North American Neuro-Ophthalmology Society |
| Holding Institution |
Spencer S. Eccles Health Sciences Library, University of Utah |
| Rights Management |
Copyright 2002. For further information regarding the rights to this collection, please visit: https://NOVEL.utah.edu/about/copyright |
| ARK |
ark:/87278/s6zp73qd |
| Setname |
ehsl_novel_shw |
| ID |
188569 |
| Reference URL |
https://collections.lib.utah.edu/ark:/87278/s6zp73qd |
