| Identifier |
Familial_Amyotrophic_Lateral_Sclerosis |
| Title |
Familial Amyotrophic Lateral Sclerosis |
| 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 |
Supranuclear Paralysis of Up and Downgaze Degeneration; Convergence Insufficiency; Slow Hypometric Horizontal Saccades; Saccadic Breakdown of Horizontal Pursuit; Bulbar Palsy; Familial Amyotrophic Lateral Sclerosis; Lou Gehrig's Disease; CNS -Degeneration; Superoxide Dismutase (SOD1) Gene |
| History |
This 58 year old woman was referred to Dr. Robert Brown in March 1995 for evaluation of slurred speech. She remained under his care until her death. On examination she had signs of a pseudobulbar palsy: Dysarthria and dysphagia Diminished palatal movement with positive gag bilaterally Diminished rapid movements of the tongue A 1+ jaw jerk Muscle tone throughout was minimally increased and the deep tendon reflexes were hyperreflexic bilaterally. Electromyographic studies scanning multiple muscles for fasciculations were negative. Seven months later in September 1995, her speech was unintelligible and her palate hardly moved at all. She had strong eye closure but mouth opening was weak and she had bifacial weakness. Her reflexes remained brisk throughout. Urine studies for heavy metals, arsenic, cadmium, lead and mercury were negative. Repeat electromyographic studies now showed a picture of widespread denervation that helped confirm the diagnosis of amyotrophic lateral sclerosis (ALS) with a progressive bulbar onset. In November 1995, she could hardly speak and she was no longer able to protrude her tongue or whistle. As her disease progressed, she became aware of difficulty walking and in April 1996 she returned for evaluation having fallen on two occasions. By this time she had lost the ability to speak and was mute. She had difficulty chewing and swallowing, particularly liquids, and noted some difficulty as well with closing her eyes and focusing. On examination, she was mute, smiling and laughing readily with some emotional lability. She had slowing of her eye movements and impaired eyelid closure but she closed her eyes when sleeping. She was unable to smile fully on a volitional basis although when she was amused she had a full smile. The tongue could only be protruded approximately 0.5 cm. beyond the teeth with absent lateral movements. There was no atrophy of the tongue or fasciculation. In September 1996 she had a G-tube placed. Progressive weakness of the legs led to her becoming completely paralyzed from the waist down and she was confined to a wheelchair by September 1997. There was no evidence of respiratory distress. A neurovisual exam at that time, eighteen months after the onset of ALS, documented • A supranuclear paralysis of saccadic upgaze greater than downgaze with intact vertical pursuit • Slow horizontal gaze to right and left with the patient needing to move her head and eyes to look to either side • Saccadic horizontal pursuit • Convergence insufficiency with an exophoria on alternate cover test fixating on a near target • Slow volitional eye closure with preserved spontaneous eyelid opening and reflex blinking to threat and a loud noise. • No square wave jerks or nystagmus. Family history is significant for a mother who died of ALS at age 60 after a two year illness. Her mother had one sister who died without neurologic disease at age 80. The patient has two siblings who are without neurologic disease. She herself has 3 children, the oldest is age 37. The patient's DNA was tested for a mutation of the superoxide dismutase (SOD1) gene and was negative. The Vinculum Associated Binding Protein (VABP) gene had not been discovered at this time. The patient's ALS continued to progress, with predominantly upper motor neuron bulbar signs and spasticity of the limbs. She died in 1998. No autopsy was performed. |
| Anatomy |
ALS is the most common form of adult motor neuron disease; it affects both upper and lower motor neurons and has a fairly consistent clinical picture and outcome. This patient presented with an upper motor neuron progressive bulbar palsy and impairment of eye movements. The supranuclear vertical saccadic palsy for up and down gaze localizes to the midbrain and to the riMLF. The slow horizontal hypometric saccades to the right and to the left localizes to the pontine paramedian reticular formation. ALS usually spares eye movements until very late in the course of the disease despite severe weakness of the skeletal and bulbar muscles. Neuropathological studies have indicated that the oculomotor neurons themselves are spared except in very advanced cases. (9, 10). The sparing of ocular motor neurons has been related to lower concentrations of glycinergic and muscarinic receptors and to differences in glutamate transporter molecules compared with motor neurons in other nuclei affected by ALS (12). Eye movement recordings in ALS patients show the velocities and latencies of visually guided saccades are normal. Memory guided saccades are inaccurate with increased errors in the anti saccade task. Findings that are consistent with frontal lobe involvement in ALS. Square wave jerks are more frequent in ALS cases than in age matched control subjects. Impaired or asymmetric smooth pursuit has been reported. (10). Standing apart from this general picture is a subset of patients in whom impaired vertical eye movements are more prominent early in the course. Such patients usually show slowing of vertical saccades, impairment of smooth pursuit and gaze evoked nystagmus (4, 5, 8). This patient is a rare example of the early impairment of vertical gaze and slow horizontal saccadic eye movements. The localization of pathological changes in the rostral interstitial nucleus of the medial longitudinal fasciculus (riMLF) in the midbrain has been reported by Averbuch-Heller et al in two patients with ALS who had supranuclear vertical gaze impairment with slow vertical saccades.(2) In patient #1 the abnormal eye movements were noted four years after the onset of ALS, and in patient #2 three years after he developed ALS. Averbuch-Heller et al's report is of special interest in relation to the present case. Her second patient (patient #2) had difficulty opening his eyes. After completely closing his eyes he had a delay of 10 to 15 seconds initiating eye opening. The selective deficit of vertical saccades in Averbuch-Heller's patients was fully explained by marked neuronal loss in the riMLF bilaterally. Ubiquitin-positive intracytoplasmic inclusion bodies were prominent in the nuclei of the posterior commissure and present throughout the ocular motor regions of both brains including the riMLF, peri-aqueductal grey and central caudal nuclear region of the ocular motor nuclei. Mild neuronal dropout was also noted in the pontine paramedian reticular formation and in the omnipause neurons in the raphe interpositus nucleus, the medial vestibular nucleus and the nucleus repositus hyperglossi. |
| Pathology |
Averbuch-Heller L, Helmchen C, Horn AKE, Leigh JR, Büttner-Ennever JA. studied eye movements and brainstem pathology in 2 patients with slow vertical saccades and autopsy-proven ALS. In both patients, the main ocular motor finding was supranuclear vertical gaze impairment with slow vertical saccades. The second patient had difficulty initiating opening his eyes on command, with preserved spontaneous eyelid opening. Postmortem examination in both patients demonstrated cell loss in the riMLF and substantia nigra, along with histopathological findings consistent with ALS. (Figures 4-6). The extent of the pathological changes in the riMLF correlated well with the degree of functional impairment as reflected in the slow vertical saccades. The authors suggest that motor neuron disease with early involvement of vertical saccades represents a distinct clinicopathological entity. |
| Disease/Diagnosis |
Amyotrophic Lateral Sclerosis - Lou Gehrig's Disease. |
| Clinical |
This 60 year old woman with Familial Amyotrophic Lateral Sclerosis (FALS) has the following constellation of eye signs: • A supranuclear paralysis of saccadic upgaze greater than downgaze with intact vertical pursuit • Slow horizontal gaze to right and left with the patient needing to move her head and eyes to look to either side • Saccadic horizontal pursuit • Convergence insufficiency with an exophoria on alternate cover test fixating on a near target • Apraxia of volitional eye closure with preserved spontaneous eyelid opening and reflex blinking to threat and a loud noise. • No square wave jerks or nystagmus. Confirmation that the gaze disorder is supranuclear and localized to the rostral interstitial nucleus of the medial longitudinal fasciculus (riMLF) in the midbrain is the presence of : 1) upward deviation of the eyes on forced eye closure (intact Bell's) and 2) full upward eye movements when the head is bent forward, the oculocephalic or doll's eye reflex. She also had: • Bilateral facial paresis and an upper motor neuron bulbar palsy with • Inability to protrude her spastic tongue • Brisk jaw and facial jerks and • Emotional lability Comment: The inability to initiate eyelid closure is a dysfunction of voluntary lid control due, in this patient, to disease of the motor neurons in the brainstem. The term "eyelid apraxia" is a misnomer and should be dismissed as the motor system is affected. Slow horizontal gaze to right and left with the patient needing to move her head and eyes to look to either side. Saccadic horizontal pursuit Convergence insufficiency with an exophoria on alternate cover test fixating on a near target. Apraxia of volitional eye closure with preserved spontaneous eyelid opening and reflex blinking to threat and a loud noise. No square wave jerks or nystagmus. Confirmation that the gaze disorder is supranuclear and localized to the rostral interstitial nucleus of the medial longitudinal fasciculous (riMLF) in the midbrain is the presence of : 1) upward deviation of the eyes on forced eye closure (intact Bell's) and 2) full upward eye movements when the head is bent forward, the oculocephalic or doll's eye reflex. She also had: Bilateral facial paresis and an upper motor neuron bulbar palsy with -Inability to protrude her spastic tongue -Brisk jaw and facial jerks and -Emotional lability |
| Presenting Symptom |
Slurred speech |
| Ocular Movements |
Supranuclear Paralysis of Up and Downgaze; Convergence Insufficiency; Slow Hypometric Horizontal Saccades; Saccadic Pursuit |
| Neuroimaging |
No MR scans are available in this patient. Imaging from two other patients with ALS are illustrated. Case 1. Figure 1. Axial T2WI shows hyperintensity in both cerebral peduncles. Figure 2. Coronal T2WI shows the hyperintensity extending along both corticospinal tracts. Figure 3. In a second case with acute onset ALS, a series of three diffusion-weighted MR images show restricted diffusion in the ventral midbrain (prerubral region), which extends along both corticospinal tracts from the subcortical white matter inferiorly through the cerebral peduncles and medulla. Courtesy Anne Osborn, M.D. |
| Treatment |
There is no cure for ALS and once the disease has begun, its course is relentlessly progressive. |
| Etiology |
In 1993 mutations of the gene cytosolic copper-zinc superoxide dismutase (SOD1) were discovered in patients with FALS (11). This mutation is present in approximately 25% of all cases of FALS. The discovery of the SOD1 mutation resulted in a major break through in understanding not only familial ALS but also the process of cell death of motor neurons in general. (3) In 2004 a second gene was discovered, vesicle-associated membrane protein/synaptobrevin-associated membrane protein B (VAPB) which is found to be present in 5% of FALS cases. (7) View Amyotrophic Lateral Sclerosis: Perspectives from Genetics. |
| References |
1. Andersen PM. The genetics of amyotrophic lateral sclerosis (ALS). Suppl Clin Neurophysiol. 2004;57:211-227. http://www.ncbi.nlm.nih.gov/pubmed/16106621 2. Averbuch-Heller L, Helmchen C, Horn AKE, Leigh RJ, Buttner-Ennever JA. Slow vertical saccades in motor neuron disease: correlation of structure and function. Ann Neurol 1998;44:641-648. http://www.ncbi.nlm.nih.gov/pubmed/9778263 3. Brown RH Jr. Superoxide dismutase and familial amyotrophic lateral sclerosis: new insights into mechanisms and treatments. Ann Neurol 1996;39:145-146. http://www.ncbi.nlm.nih.gov/pubmed/8967744 4. Cudkowicz ME, McKenna-Yasek D, Sapp PE et al. Epidemiology of mutations in superoxide dismutase in amyotrophic lateral sclerosis. Ann Neurol 1997;41:210-221. http://www.ncbi.nlm.nih.gov/pubmed/9029070 5. Gizzi M, DiRocco A, Sivak M, Cohen B. Ocular motor function in motor neuron disease. Neurology 1992;42:1037-1046. http://www.ncbi.nlm.nih.gov/pubmed/1579227 6. Kushner MJ, Parrish M, Burke A, Behrens M, Hays AP, Frame B, Rowland LP. Nystagmus in motor neuron disease: clinicopathological study of two cases. Ann Neurol 1984;16:71-77. http://www.ncbi.nlm.nih.gov/pubmed/6465863 7. Leigh RJ, Zee DS. Diagnosis of Central Disorders of Ocular Motility. Chp 12:598-718. In: The Neurology of Eye Movements, Fourth Edition. Oxford University Press, NY. 2006. 8. Marti F, Roig C. Oculomotor abnormalities in motor neuron disease. J Neurol 1993;240:475-478. http://www.ncbi.nlm.nih.gov/pubmed/8263553 9. Mizutani T, Aki M, Shiozawa R, Unakami M., Nozawa T, Yajima K, Tanabe H, Hara M. Development of ophthalmoplegia in amyotrophic lateral sclerosis during long-term use of respirators. J Neurol Sci 1990;99:311-319. http://www.ncbi.nlm.nih.gov/pubmed/2086731 10. Nishimura AL, Mitne-Neto M, Silva HC, Richieri-Costa A, Middleton S, Cascio D, Kok F, Oliveira JR, Gillingwater T, Webb J, Skehel P, Zatz M. A mutation in the vesicle-trafficking protein VAPB causes late-onset spinal muscular atrophy and amyotrophic lateral sclerosis. Am J Hum Genet. 2004 Nov;75(5):822-31. http://www.ncbi.nlm.nih.gov/pubmed/15372378 11. Okamoto K, Hirai S, Amari M, Iizuka T, Watanabe M., Murakami N. Takatama M. Oculomotor nuclear pathology in amyotrophic lateral sclerosis. Acta Neuropathol. 1993;85:458-462. http://www.ncbi.nlm.nih.gov/pubmed/8493857 12. Rosen DR. Mutations in Cu/Zn superoxide dismutase gene are associated with familial amyotrophic lateral sclerosis. Nature 1993;362:59-62. http://www.ncbi.nlm.nih.gov/pubmed/8446170 13. Whitehouse PJ, Wamsley JK, Zarbin MA, Price DL, Kuhar MJ. Neurotransmitter receptors in amyotrophic lateral sclerosis: possible relationship to sparing the eye movements. Ann Neurol 1985;17:518. http://www.ncbi.nlm.nih.gov/pubmed/2988415 |
| Language |
eng |
| Format |
application/pdf |
| Format Creation |
Microsoft PowerPoint |
| Type |
Text |
| Relation is Part of |
944-6 |
| 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/s6cmsqny |
| Setname |
ehsl_novel_shw |
| ID |
2174199 |
| Reference URL |
https://collections.lib.utah.edu/ark:/87278/s6cmsqny |
