| Identifier |
Frontotemporal_Dementia |
| Title |
Frontotemporal Dementia |
| Creator |
Shirley H. Wray, MD, PhD, FRCP |
| Affiliation |
(SHW) Professor of Neurology, Harvard Medical School; Director, Unit for Neurovisual Disorders, Massachusetts General Hospital, Boston, Massachusetts |
| Subject |
Saccadic Initiation Deficit of Unilateral Horizontal Gaze; Complete Paralysis of Voluntary Horizontal Saccades on Command to Look Left; Inability to Make a Refixation Saccade on Command to a Target Held on the Left; Normal Voluntary Horizontal Saccadic Eye Movements to the Right; Impaired Pursuit; Frontotemporal Dementia; Picks Disease; CNS Degeneration; Acquired Oculomotor Apraxia; Acquired Ocular Motor Apraxia |
| History |
The patient is a 68 year old right handed retired air conditioner repair man who presented with impaired balance and slow walking. For about one year he had noted difficulty lifting his feet high enough when climbing the stairs. From that time on, his movements slowed and worsened so that he had difficulty dressing, using a knife and fork, and getting in and out of a chair. His walk became slow and unsteady and his balance was poor. Because of impaired balance, he needed to sit to put his trousers on. His writing became less legible and his speech slow and hesitant. When answering a question, he often had to repeat the question before giving the answer. The patient denied any visual symptoms except trouble judging space and distance. He reported having a minor car accident when he drove 100 feet in reverse without putting his foot on the brake pedal. He stopped only because he hit his garage door. He had noticed no trouble with memory, no confusion, no difficulty finding words or understanding speech. He also denied weakness, stiffness, tremors, numbness, headache or syncope. He had no visual complaints. Social History: Retired age 65. No history of alcohol abuse. Past History: Negative for cardiac disease, stroke or head trauma. In 1975 (fifteen years ago), he had an attack of the Guillian Barre Syndrome causing total paralysis and difficulty breathing. He was not on a respirator. He returned to normal activity and work in six to eight weeks. Family History: Negative for CNS disease. His family, concerned that his "slowing up" might be due to Parkinson's disease, consulted his primary care doctor. He was then referred to Dr. Raymond Adams for an opinion. On examination his speech was slow and hesitant without paraphasic errors. In following commands or answering questions, he repeated the command or question prior to proceeding (echolalia (repetition of the utterance of others)). He repeated "no ifs, ands or buts" and spelled the word ‘world' correctly but could not spell it backwards. He was fully oriented and remembered the President, Vice President and immediate past President but not who preceded Reagan. He was unable to subtract serial 7's beyond 93. He made one error in the Tom and Bill story after ten minutes. Writing was tremulous and poorly legible, with correct spelling. He was able to draw a clock and bisect a line correctly. He had some difficulty copying a complex drawing. There was no limb apraxia, but his truncal movements seemed apraxic. Tendon reflexes were 1+ and symmetric, plantars flexor. He had frontal lobe release signs. Sensation and coordination were normal. The neurovisual exam documented: Visual acuity 20/30 OU Visual field testing showed impaired localization of a visual stimulus in space on the tangent screen. He pointed lateral to the location of the stimulus target by about an inch both in the right half and left half field and in both superior and inferior quadrants. Pupils equal, normal reflexes Ocular motility: (See below for constellation of eye signs) Mild age-related ptosis Saccadic initiation deficit of unilateral horizontal gaze A complete paralysis of voluntary horizontal saccades on command to look left Inabililty to make on command a refixation saccade to a target held on the left (including his own hand) Normal voluntary horizontal saccadic eye movements to the right No saccadic intrusions No apraxia of eyelid closure No nystagmus Normal optokinetic nystagmus Normal optic discs and fundi OU Brain MRI showed global generalized central and cortical atrophy with frontal cortex and temporal lobes most affected bilaterally. Neuropsychological Testing by Dr. Janet Sherman showed a general depression of intellectual function as well as many specific cognitive deficits. The deficits which the patient displayed were suggestive of frontal lobe damage. Behavioral Observations: He was noted to have greatly diminished verbal output. His speech was slow and hesitant with normal articulation. He was noted to be echolalic consistently repeating what was said to him. During the examination he became agitated even angry at times. Tasks that were difficult for him he refused to do. General Intellectual Function: As assessed by the Wechsler Adult Intelligence Scale-Revised, his full scale IQ was 75 (in the borderline range), verbal IQ 73 and performance IQ 78. These scores are indicative of significantly depressed intellectual function. Visuospatial/Visuomotor Abilities: On the Judgment of Line Orientation Test his performance was severely defective suggesting a significant disturbance in spatial perception and orientation. His constructional abilities were also depressed. His ability to construct block designs copied from a model was in the low end of the low average range. On a number and letter sequencing task, he displayed perseverative movements, for example, going back and forth over already drawn lines. His motor speed on a peg board task was severely impaired. Attention/Memory: His mental control abilities were impaired for rapidly counting backwards from 20 to 1, for rapidly reciting the alphabet and for rapidly counting by 3's from 1 to 40. He was able to repeat only 4 digits forward and only 3 backward. The patient's memory for verbal material, particularly for stories fell in the 52 percentile for immediate memory, but only at the 7 percentile for delayed (20 minutes) recall. In a recognition task, he identified all but 2 of the 16 items on the initial list that was presented, and did not falsely confirm any of the items that were not on the list. His good recognition memory suggested that his memory problems may not be related to encoding or storage of information, but rather to retrieval of that information. Both his immediate and delayed drawings were noted to lack many of the figures' organizational features, particularly as the figures became more complex. Language: The patient's confrontation naming abilities fell 3 standard deviations below the mean for his age level. In addition to his word finding difficulties, his verbal and written fluency was significantly impaired. Abstract Reasoning: His abstract reasoning abilities were severely impaired; he was unable to state how an orange and a banana were alike, and denied that words such as a coat and a suit, a boat and automobile and an eye and ear had any similarity. Summary: The deficits exhibited by this patient were: Greatly diminished verbal output Perseverative tendencies An extreme stimulus boundedness; for example, he picked up any object placed in front of him, such as the examiner's coffee cup or pencil and had difficulty releasing the object A greatly decreased verbal fluency The Cognitive Syndrome displayed: • A general depression in intellectual function • Extreme demonstration of frontal lobe signs suggestive of circumscribed "cortical atrophy" which is often associated with Pick's Disease Dr. Sherman was of the opinion that the intellectual decline which the patient exhibited was less suggestive of Alzheimer's Disease where memory impairments are usually an early feature. She considered the memory impairments that he exhibited were suggestive of a "frontal amnesia", where patients tend to assert that they cannot remember something, but when prompted they produce some responses. The patient often stated he could remember nothing, but when encouraged to reply, or when given cues as in the recognition memory test, his recall was quite good. Dr. Adam's diagnosis was Frontotemporal Dementia - a behavioral syndrome due to degeneration of the frontal and anterior temporal lobes. In advanced cases marked frontal and anterior temporal atrophy is prominent on the medial and lateral views of the affected hemisphere. The initial presentation may be altered by the areas involved. Subjects with frontal involvement have significant apathy, whereas those with temporal involvement have significant hypomanic behavior, puerile and emotional behaviors. Depression and anxiety correlate with right-sided temporal change and irritability and aggressive outbursts with left sided temporal changes. These findings can help in the initial clinical diagnosis of this variably expressed disorder. |
| Anatomy |
The brain controls how the eyes move by processing information in multiple, distinct, well delineated cortical regions called eye fields. Three eye fields in the frontal lobes contribute to the control of eye movements: The frontal eye field (FEF), the supplementary eye field (SEF) and the dorsolateral prefrontal eye field (DLPEF) initiate saccadic and pursuit eye movements by delivering trigger signals to the brainstem oculomotor circuits. Lesions affecting each of these areas produce distinctive behavioral deficits. Box 12-21 Effects of Frontal Lobe Lesions p.661 (6) The FEF is located around the lateral part of the precentral sulcus, involving adjacent areas of the precentral gyrus, the middle frontal gyrus, and the superior frontal gyrus. The FEF corresponding to confluent portions of Brodmann areas 6 and 4, but not 8. A unilateral lesion that inactivates the FEF inhibits the initiation of contralateral voluntary saccades, as illustrated by this case. Acute lesions of the FEF may produce an ipsilateral horizontal gaze deviation that resolves with time. FEF lesions also impair smooth pursuit. With unilateral FEF lesions, horizontal pursuit is impaired bilaterally, but more so for tracking targets moving to the side of the lesion. Both the initiation and maintenance of pursuit are affected, especially at fast target speeds. The defect that is characteristic of SEF lesions is a loss of ability to make a sequence of saccades to an array of visible targets in the order that the targets appear. Patients with lesions affecting the PFEF show a defect of memory-guided saccades, antisaccades, and predictive saccades. Bilateral pursuit defects may be present with unilateral PFEF lesions. |
| Pathology |
The brains of patients with FTD show a lobar distribution of atrophy involving the frontal lobes, temporal lobes, or both. The orbitofrontal cortex and the anterior and medial temporal areas show the most severe atrophic changes. The atrophy is bilaterally symmetric in approximately 30% of cases, has a left-sided predominance in 50%, and involves primarily the right side in 20%. An abrupt transition is sometimes evident between involved and uninvolved cortical regions, particularly with Pick Disease. The initial presentation may be altered by the areas involved (2, 6). Subjects with frontal involvement have significant apathy, whereas those with temporal involvement have significant hypomanic, puerile or labile behaviors. Right-sided temporal deficits cause hypomanic and irritability. Left sided temporal deficit cause mood swings. There are several major neuropathologic variants of frontotemporal lobar degeneration (FTLD). They include FTLD and argentophilic intranuclear inclusions (Pick bodies). FTLD-lacking distinctive histology (FTLD-ldh) and motor neuron disease-Inclusion Dementia or Corticobasal Degeneration (CBD). All these conditions have circumscribed and progressive atrophy of restricted brain regions with microvascular changes in superficial layers and astrocytic glyosis. Kertesz et al suggested the term Pick Complex to signify their cohesion. Converging evidence suggests that at least some of these disorders are tauopathies from tau protein abnormalities in the brain and many have mutations in the tau gene on chromosome 17. In 1892, Arnold Pick described a patient with a unique dementing disease and circumscribed atrophy of the left temporal lobe. An autopsy revealed frontotemporal lobar degeneration and argentophilic intranuclear inclusions (Pick bodies). These histologic changes occur in advance of overt clinical signs. Pick bodies are spherical, slightly basophilic intraneuronal cytoplasmic inclusions on luxol fast blue, hemotoxylin and eosin stain composed of 100Ã… neurofilaments and 240Ã… neurotubules. Pick bodies are strongly argentophilic on Bielschowski stain and other silver stains. Pick bodies are concentrated in frontotemporal neocortical layers and the hippocampal formation in the granular layer of the dentate gyrus and in sector CA1. Pick bodies do not occur in normal aging. Both antibodies against phosphorylated tau protein and antiubiquitin antibodies stain Pick bodies. Pick disease is now classified as a tauopathy. |
| Disease/Diagnosis |
Frontotemporal Dementia/Pick Disease - Tauopathy |
| Clinical |
This patient with frontotemporal dementia (FTD) has: • Saccadic initiation deficit of unilateral horizontal gaze • A complete paralysis of voluntary horizontal saccades on command to look left • Inabililty to make on command a refixation saccade to a target held on the left (including his own hand) • Normal voluntary horizontal saccadic eye movements to the right • No saccadic intrusions Key eye movement signs confirming cortical localization are: • Pursuit eye movements are impaired in all directions of gaze (possibly due to lack of fixation) • The presence of normal horizontal optokinetic nystagmus (fast phase) • Occasional horizontal leftward gaze on random eye movements • Intact horizontal eye movements on passive head turn (oculocephalic reflex ), doll's eye reflex Patient also has: • A flat affect • Echolalia (repetition of the utterances of others) • Bilateral age related asymmetrical ptosis. Comment Dr. Zee (DZ) July 2006 DZ: So this case brings up the difficulty in sorting out the term acquired ocular motor apraxia. A term shunned by some people and somewhat put forth by Charles Pierrott Deseilligny though I would agree with you that the better term is saccadic initiation deficit. This man seems to have difficulty initiating saccades at a more voluntary level than at a more reflexive level which would speak for a more anterior cortical lesion. The usual differential would be the posterior variant of Alzheimer's disease with a simultaneous agnosia, optic ataxia and some psychic paralysis of gaze - with difficulty directing their eyes. SHW: Can we call this may be an apraxia of gaze to one side only? DZ: I would not use the word apraxia. I think this is a saccade initiation deficit. There is a paper that came out 48 hours ago that I saw on studying saccades in patients with different types of dementia. It's in the Journal of Neuroscience. The investigators studied MRI of the frontal eye fields in patients with frontal lobe degeneration and looked at defects in initiation of saccades and suppression of reflexive saccades. I am going to send it to you to read. SHW: Wonderful. See Ref. Boxer AL et al. Medial Versus Lateral Frontal Lobe Contributions to Voluntary Saccade Control as Revealed by the Study of Patients with Frontal Lobe Degeneration. J of Neurosci 2006, 26(23); 6354-6363. |
| Presenting Symptom |
Motor slowing and cognitive changes |
| Ocular Movements |
Saccadic initiation deficit of unilateral horizontal gaze; Complete paralysis of voluntary horizontal; saccades on command to look left; Inability to make a refixation saccade on command to a target held on the left; Normal voluntary horizontal saccadic eye movements to the right; Impaired pursuit |
| Neuroimaging |
Brain MRI was not available in this patient. MRI findings in another case are shown here. Figure 1. Imaging in a patient with classic FTD is shown on these scans. Another axial NECT scan shows disproportionate frontal atrophy with "knife-like" gyri. Figure 2. Sagittal T1-weighted MR scan shows the frontal sulci are more prominent than the parietal and occipital sulci. Figure 3. Coronal T2-weighted scan shows the "knife-like" shrunken, atrophic gyri in both frontal lobes. The temporal lobes are relatively spared. Courtesy Anne Osborn, M.D. Single photo emission tomography (SPECT) and PET scans show decreased regional cerebral blood flow and hypometabolism in the frontal cortex and anterior temporal lobes compared to a normal aging brain. The changes are often asymmetric and this is especially helpful in diagnosis. The lack of specificity, however, limits the contribution of functional imaging for diagnosis. |
| Treatment |
Although there is no specific treatment for FTD, symptomatic therapies can be very helpful, and many of the behavioral symptoms; for example, depression and compulsion may respond to serotonin selective re-uptake inhibitors (SSRIs). |
| Etiology |
The underlying cause of FTD is unknown but genetic factors play a role. A positive family history of a similar dementia in a first-degree relative is present in as many as 38 to 50% of patients with FTD. About 50% of familial FTD patients have genetic forms mapped to chromosome 17q 21-22. (3, 7, 9). The gene mutations that can lead to FTD include tau, progranulin, TDP-43, valosin and CHMP2B. The concept of tauopathies and TDP-43 opathies is discussed by Trojanowski in his F.B. Bennett Memorial Lecture at the American Neurological Association Meeting in 2008. (See attached) |
| References |
1. Boxer Al, Garbutt, S, Rankin KP, Hellmuth J, Neuhaus J, Miller BL and Lisberger SG. Medial Versus Lateral Frontal Lobe Contributions to Voluntary Saccade Control as Revealed by the Study of Patients with Frontal Lobe Degeneration. J of Neurosci 2006: 26(23):6354-6363. http://www.ncbi.nlm.nih.gov/pubmed/16763044 2. Herdman AT, Ryan JD. Spatio-temporal Brain Dynamics Underlying Saccade Execution, Suppression and Error-related Feedback. J Cogn Neurosci 2007;19:3:420-432. http://www.ncbi.nlm.nih.gov/pubmed/17335391 3. Hodges JR. Frontotemporal dementia (Pick's disease): clinical features and assessment. Neurology 2001;56:S6-10. http://www.ncbi.nlm.nih.gov/pubmed/11402143 4. Hutton M. Molecular genetics of chromosome 17 taupathies. Ann NY Acad Sci 2000;920:63-73. http://www.ncbi.nlm.nih.gov/pubmed/11193178 5. Kertesz A, Hillis. Frontotemporal dementia and Pick Disease. Ann Neurol 2003: 54(suppl5) S3. http://www.ncbi.nlm.nih.gov/pubmed/12833359 6. Leigh RJ and Zee DS. Diagnosis of Central Disorders of Ocular Motility. Ch 12; 598-718. In: The Neurology of Eye Movements, 4th Edition. Oxford University Press 2006, 7. McKhann GM, Albert MS, Grossman M, Miller B, Dickson D, Trojanowski JQ. Clinical and pathological diagnosis of frontotemporal dementia: report of the Work Group on Frontotemporal Dementia and Pick's Disease. Arch Neurol 2001;58:1803-1809. http://www.ncbi.nlm.nih.gov/pubmed/11708987 8. Pickering-Brown SM, Richardson AM, Snowden JS, McDonagh AM, Burns A, Braude W, Baker M, Liu WK, Yen SH, Hardy J, Hutton M, Davies Y, Allsop D, Craufurd D, Neary D and Mann DMA. Inherited frontotemporal dementia in nine British families associated with intronic mutations in the tau gene. Brain 2002;125:732-751. http://www.ncbi.nlm.nih.gov/pubmed/11912108 9. Rosen HJ, Gorno-Tempini ML, Goldman WP ,Perry RJ, Schuff N, Weiner M., Feiwell R, Kramer JH and Miller, BL. Patterns of brain atrophy in frontotemporal dementia and semantic dementia. Neurology 2002;58:198-208. http://www.ncbi.nlm.nih.gov/pubmed/11805245 10. Spillantini MG, Bird TD, Ghetti B. Frontotemporal dementia and Parkinsonism linked to chromosome 17: a new group of tauopathies. Brain Pathol 1998;8:387-402. http://www.ncbi.nlm.nih.gov/pubmed/9546295 11. Trojanowski JQ. TDP-43 Proteinopathy: Shared mechanisms underlying frontotemporal lobar degenerate (FTD) and amyotrophic lateral sclerosis (ALS). In press. 12. Arnold Pick - http://www.whonamedit.com/doctor.cfm/1100.html |
| Language |
eng |
| Format |
application/pdf |
| Format Creation |
Microsoft PowerPoint |
| Type |
Text |
| Relation is Part of |
925-3 |
| Collection |
Neuro-Ophthalmology Virtual Education Library: Shirley H. Wray 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/s62q14h9 |
| Setname |
ehsl_novel_shw |
| ID |
2174200 |
| Reference URL |
https://collections.lib.utah.edu/ark:/87278/s62q14h9 |
