| Identifier |
945-5 |
| Title |
Saccadic Initiation Deficit of Horizontal Saccades |
| Creator |
Shirley H. Wray, MD, PhD, FRCP |
| Contributors |
Tessa Hedley-Whyte, MD; Anne Osborn, 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; (AO) Professor of Radiology, University of Utah, Salt Lake City, Utah; (DZ) Johns Hopkins Hospital, Baltimore, Maryland |
| Subject |
Cerebral Cortex; Selective Saccadic Palsy - Acquired; Slow Initiation of Horizontal Saccades on Command; Slow Hypometric Horizontal Saccades; Supranuclear Saccadic and Pursuit Upgaze Palsy; Slow Initiation of Horizontal Purusit Tracking a Slow Target; Positive Glabella Tap; Facial Tremor; Alzheimer's Disease with Mild Extrayramidal Signs; CNS Degeneration |
| History |
The patient is a 78 year old left handed woman with a diagnosis of a left parietal infarct in 1995, bilateral carotid artery stenosis and hypertension. She was first seen in August 1997 for evaluation of involuntary movements of the lower face in the setting of rapidly progressive dementia and was admitted to hospital with a presumptive diagnosis of CNS Whipple's Disease. The patient was an executive secretary and retired some years ago. She had been an avid reader, and had enjoyed a very high functioning life and dressed meticulously. In late 1996, she developed some "psychiatric difficulties" and the visiting nurse became concerned. According to the care giver, the patient then had a dramatic decline with the onset of confusion, forgetfulness, and inability to care for herself and remain independent. She was admitted to a nursing facility where she disturbed other patients by climbing into their bed. A neurologist confirmed that she was demented and noted that her body and limb movements were generally bradykinetic. She walked without swinging her arms and turned en bloc. She was minimally interactive but pleasant and reasonably cooperative with the examiner. She had a tremor of the chin, lips and throat, but no apparent dysarthria and no resting tremor of the limbs. In the upper extremities, there was an increase in tone of the cog wheel type. The reflexes were brisk throughout and the plantar responses were equivocal. Root, snout and suck reflexes were present and Hoffman and Wartenberg's signs were also mildly present. The glabella tap was positive. Sensation to all modalities throughout was normal. Differential Diagnosis of Dementia. Top of the list, as the commonest cause of Dementia in the US is Alzheimer's Disease, which was the diagnosis in this patient. It was essential, however, to exclude: 1) Whipple's Disease 2) Paraneoplastic Limbic Encephalitis 3) Progressive Supranuclear Palsy (PSP) and, less likely 4) Creutzfeld-Jakob Disease (CJD) in the absence of myoclonus and ataxia Alzheimer's Disease (AD) The criteria for probable AD include the presence of dementia, progressive worsening of memory and other cognitive functions, deficits in two or more areas of cognition, no disturbance of consciousness, age of onset between 40 and 90, and the absence of systemic or central nervous system disorders that could account for the dementia. Use of these clinical criteria has yielded diagnostic accuracy in autopsy series of greater than 80%. Whipple's Disease is characterized by a supranuclear paralysis of vertical up and down gaze (See #932-1) and progressive dementia. In this case Whipple's was ruled out by a normal jejunal biopsy, a normal stereotactic brain biopsy and a negative PCR for Whipple's on the CSF. Paraneoplastic Limbic Encephalitis was considered and ruled out by negative serology for antibodies associated with paraneoplastic disease including anti-Yo, anti-Ri, and anti-Hu. PSP was seriously considered because of the overlap of many clinical signs i.e. 1. Extrapyramidal features of her face with a positive Glabella tap, plus cogwheel rigidity of the limbs and bradykinesia 2. A brisk jaw and facial jerks 3. Slow saccadic eye movements i.e. a Slow Saccade Syndrome. A significant negative for PSP was the absence of a supranuclear vertical downgaze palsy. CJD was ruled out by documentation of normal serial EEG recordings. |
| Anatomy |
The cognitive profile seen in AD is consistent with the distribution of pathology in this disease. In the early stages, pathologic changes, especially the accumulation of neurofibrillary tangles, tend to involve limbic regions and over time spread to neocortical areas. The temporolimbic system plays a central role in memory processing and pathology in this region helps to explain the salient memory disturbance observed in AD. |
| Pathology |
AD is characterized pathologically by senile plaques (composed of dystrophic neuritis and a central core of extracellular deposits of Aβ), neurofibrillary tangles (composed of paired helical filaments that contain an abnormally phosphorylated protein), significant loss of neurons, and diminished synaptic density. The limbic system and multimodal association areas are particularly ravaged, with the relative sparing of primary motor and sensory cortex. The cholinergic system, arising from the basal forebrain, is significantly disrupted, and many other neurotransmitter systems are damaged affecting multifocal areas of cortex involved in different aspects of cognition. According to the amyloid cascade hypothesis, amyloid-beta peptide (Aβ) plays a central role in the pathogenesis of the disease. AD results from excessive production or diminished clearance of Aβ. This 40-42 aminoacid protein is produced through the cleavage of βamyloid precursor protein (APP) by proteases that have been designated β-secretase and γ-secretase. It has been recognized that excessive Aβ leads to progressive neuronal damage, perhaps through inflammatory and oxidative injury. The value of CSF markers for very early or preclinical diagnosis remains to be determined. |
| Disease/Diagnosis |
Alzheimer Disease |
| Clinical |
This 78 year old woman with dementia was unable to recall that she had seen the examiner only three days previously replying it was "10 years", and unable to name the name of the hospital. She incorrectly stated her age was 73 years and her date of birth 1997. She knew the year was 1997. On examination she had: 1. An essential tremor of the chin aggravated by attempting to protrude her tongue. 2. Hesitancy protruding the tongue which moved slowly from side to side. 3. Brisk jaw and facial jerks. Eliciting the left facial jerk produced a simultaneous elevation of the left eyebrow. 4. The face was expressionless and mask-like. 5. Positive Glabella tap - an inability to inhibit a blink when the forehead is tapped. She had no blepharoclonus or apraxia of eyelid opening or closure. The eye movements (EMs) show: 1. Slow initiation of horizontal saccades on command to the left side greater than to the right. 2. Slow saccade syndrome with slow hypometric horizontal saccades 3. The suggestion of a supranuclear saccadic upgaze palsy with impaired conjugate upgaze and full upgaze on doll's head maneuver fixing on a target. (Bell's reflex could not be tested as she failed to close her eyes tightly). 4. Slow initiation of pursuit EMs, horizontally and vertically, particularly pursuit of a target to the left due, in part, to lack of attention and poor fixation. Slow initiation of horizontal saccades is the key sign of localizing value. ID925-3 is a man with Frontotemporal Dementia and slow initiation of unilateral horizontal saccades to the left. This case should be reviewed alongside this patient. |
| Presenting Symptom |
Confused and forgetful |
| Ocular Movements |
Slow initiation of horizontal saccades on command; Slow hypometric horizontal saccades; Supranuclear saccadic and pursuit upgaze palsy; Slow initiation of horizontal purusit tracking a slow target; Positive glabella tap |
| Neuroimaging |
No imaging studies are available in this patient. MRI in AD has demonstrated significant focal atrophy of the brain in patients in preclinical stages. The images of two separate patients with AD are illustrated. Case 1. Figure 1. shows striking and disproportionate temporal lobe atrophy. The sylvian fissure is markedly enlarged compared to the sulci on this sagittal T1WI. Figure 2. Axial FLAIR shows the sylvian fissures are exceptionally large. Note lack of white matter signal abnormalities. Case 2. Is a patient with the Heidenhain variant of AD. in this case. Figure 3. Axial T1WI shows remarkable enlargement of the occipital horns with relative sparing of the temporal horns. Figure 4. T2WI: The occipital cortex is thinned and atrophic. Functional MRI with, single photon emission computed tomography (SPECT), has suggested that the most typical pattern in probable AD is bilateral temporoparietal hypoperfusion, with a variable degree of additional bifrontal perfusion abnormalities. Older adults in the preclinical stage of AD exhibit hypoperfusion of medial temporal, anterior and posterior singulate, and thalamic regions. |
| Treatment |
Treatment goals for AD are similar to those for all dementing diseases and include eliminating or managing other conditions that contribute to further decline of a patient's cognitive and functional status, treating cognitive and behavioral symptoms, slowing the rate of disease progression, delaying the onset of disease (note that a 5 year delay in onset would reduce the number of AD cases by 50%), and preventing disease development. (5) |
| Etiology |
There are currently four known Alzheimer's genes. Three are: Amyloid precursor protein, Presenilin 1, Presenilin 2 are early onset genes, which means mutations in these genes usually cause AD in the individual before that person reaches age 60. More over, the early onset gene mutations are sufficient to cause the disease with certainty. The fourth Alzheimer's gene is, APOE, which is a late onset gene which begins to impact persons with a particular variant of the gene (APOE4) from the age mid-60's and onward. This gene variant increases risk for AD but does not guarantee onset. Together, these four known genes account for approximately 30% of the genetic under pinnngs of AD. Additional Alzheimer genes remain to be discovered and account for the remaining 70% of the genetic basis of the disease. |
| Supplementary Materials |
PowerPoint Presentations: Alzheimer's Disease: https://collections.lib.utah.edu/details?id=2174175 Brain Control of Horizontal Saccadic Eye Movements: https://collections.lib.utah.edu/details?id=2174180 |
| Date |
1997 |
| References |
1. Avramopoulos D, Fallin MD, Bassett SS. Linkage to chromosome 14q in Alzheimer's disease (AD) patients without psychotic symptoms. Am J Med Genet B Neuropsychiatr Genet. 2005 Jan 5;132(1):9-13. http://www.ncbi.nlm.nih.gov/pubmed/15389761 2. Chang JB, Wang PN, Chen WT, Liu CY, Hong CJ, Lin KN, Liu TY, Chi CW, Liu HC. ApoE epsilon4 allele is associated with incidental hallucinations and delusions in patients with AD. Neurology. 2004 Sep 28;63(6):1105-7. http://www.ncbi.nlm.nih.gov/pubmed/15452311 3. Holroyd S, Shepherd ML. Alzheimer's disease: a review for the ophthalmologist. Surv Ophthalmol. 2001 May-Jun;45(6):516-24. Review. http://www.ncbi.nlm.nih.gov/pubmed/11425357 4. McIlroy S, Craig D. Neurobiology and genetics of behavioural syndromes of Alzheimer's disease. Curr Alzheimer Res. 2004 May;1(2):135-42. Review. http://www.ncbi.nlm.nih.gov/pubmed/15975078 5. Samuels MA, Feske SK. Alzheimer's Disease: Diagnosis, Pathophysiology, and Treatment. Part VI; Section 1:137. In: Office Practice of Neurology, 2nd Edition. Elsevier Science USA, 2003. 6. Selkoe DJ. Toward a remembrance of things past: deciphering Alzheimer disease. Harvey Lect. 2003-2004;99:23-45. Review. http://www.ncbi.nlm.nih.gov/pubmed/15984550 7. St George-Hyslop PH, Petit A. Molecular biology and genetics of Alzheimer's disease. C R Biol. 2005 Feb;328(2):119-30. Review. http://www.ncbi.nlm.nih.gov/pubmed/15770998 8. Kurlan R, Richard IH, Papka M, Marshall F. Movement disorders in Alzheimer's disease: more rigidity of definitions is needed. Mov Disord. 2000 Jan;15(1):24-9. Review. http://www.ncbi.nlm.nih.gov/pubmed/10634238 9. Louis ED. Essential tremor. Lancet Neurol. 2005 Feb;4(2):100-10. Review. http://www.ncbi.nlm.nih.gov/pubmed/15664542 10. Alois Alzheimer: http://www.whonamedit.com/doctor.cfm/177.html |
| Language |
eng |
| Format |
video/mp4 |
| Type |
Image/MovingImage |
| Source |
3/4" Umatic master videotape |
| Relation is Part of |
924-2, 925-3; 932-1, 932-3, 936-5, 939-3, 946-5 |
| 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/s6md1wmf |
| Setname |
ehsl_novel_shw |
| ID |
188564 |
| Reference URL |
https://collections.lib.utah.edu/ark:/87278/s6md1wmf |
