This document provides an overview of ataxia, including its definition, causes, clinical features, classifications, hereditary forms, and spinocerebellar ataxia (SCA). Key points include: Ataxia is caused by dysfunction of the cerebellum and its pathways, resulting in loss of coordination. Common clinical features are gait and limb ataxia, dysarthria, and gaze abnormalities. Causes include genetic, paraneoplastic, infectious, autoimmune, and others. Hereditary forms include autosomal dominant and recessive SCAs, Friedreich's ataxia, and more. SCA is the most common hereditary ataxia and subtypes are distinguished by their clinical
semiological classification of seizure, localisation and lateralisation Vinayak Rodge
Semiologial classification plays an important role in proper diagnosis and treatment of epilepsy .it also has localizing and lateralizing value which helps in epileptic surgical interventions .
This ppt describes various movement disorders found commonly in elderly persons. It also describes hyper and hypokinetic disorder categorization with cause and pathophysiology of movement disorders.
semiological classification of seizure, localisation and lateralisation Vinayak Rodge
Semiologial classification plays an important role in proper diagnosis and treatment of epilepsy .it also has localizing and lateralizing value which helps in epileptic surgical interventions .
This ppt describes various movement disorders found commonly in elderly persons. It also describes hyper and hypokinetic disorder categorization with cause and pathophysiology of movement disorders.
Ataxia (Gk. A Taxis = Order; means lack of order)
Ataxia denotes a syndrome of imbalance and incoordination involving gait, limbs, and speech and usually results from the disorder of the cerebellum or its connections
It is characterized by dyssynergia, dysmetria,mdysdiadochokinesia (Joseph Babinski).
It is a disorder of rate, range, direction and force of movements (Gordon Holmes).
Ataxia denotes a syndrome of imbalance and Incoordination involving gait, limbs, and speech and usually results from the disorder of the cerebellum or its
connections
It is characterized by dyssynergia, dysmetria, dysdiadochokinesia (Joseph Babinski).
It is a disorder of rate, range, direction and force of movements (Gordon Holmes).
micro teaching on communication m.sc nursing.pdfAnurag Sharma
Microteaching is a unique model of practice teaching. It is a viable instrument for the. desired change in the teaching behavior or the behavior potential which, in specified types of real. classroom situations, tends to facilitate the achievement of specified types of objectives.
Title: Sense of Smell
Presenter: Dr. Faiza, Assistant Professor of Physiology
Qualifications:
MBBS (Best Graduate, AIMC Lahore)
FCPS Physiology
ICMT, CHPE, DHPE (STMU)
MPH (GC University, Faisalabad)
MBA (Virtual University of Pakistan)
Learning Objectives:
Describe the primary categories of smells and the concept of odor blindness.
Explain the structure and location of the olfactory membrane and mucosa, including the types and roles of cells involved in olfaction.
Describe the pathway and mechanisms of olfactory signal transmission from the olfactory receptors to the brain.
Illustrate the biochemical cascade triggered by odorant binding to olfactory receptors, including the role of G-proteins and second messengers in generating an action potential.
Identify different types of olfactory disorders such as anosmia, hyposmia, hyperosmia, and dysosmia, including their potential causes.
Key Topics:
Olfactory Genes:
3% of the human genome accounts for olfactory genes.
400 genes for odorant receptors.
Olfactory Membrane:
Located in the superior part of the nasal cavity.
Medially: Folds downward along the superior septum.
Laterally: Folds over the superior turbinate and upper surface of the middle turbinate.
Total surface area: 5-10 square centimeters.
Olfactory Mucosa:
Olfactory Cells: Bipolar nerve cells derived from the CNS (100 million), with 4-25 olfactory cilia per cell.
Sustentacular Cells: Produce mucus and maintain ionic and molecular environment.
Basal Cells: Replace worn-out olfactory cells with an average lifespan of 1-2 months.
Bowman’s Gland: Secretes mucus.
Stimulation of Olfactory Cells:
Odorant dissolves in mucus and attaches to receptors on olfactory cilia.
Involves a cascade effect through G-proteins and second messengers, leading to depolarization and action potential generation in the olfactory nerve.
Quality of a Good Odorant:
Small (3-20 Carbon atoms), volatile, water-soluble, and lipid-soluble.
Facilitated by odorant-binding proteins in mucus.
Membrane Potential and Action Potential:
Resting membrane potential: -55mV.
Action potential frequency in the olfactory nerve increases with odorant strength.
Adaptation Towards the Sense of Smell:
Rapid adaptation within the first second, with further slow adaptation.
Psychological adaptation greater than receptor adaptation, involving feedback inhibition from the central nervous system.
Primary Sensations of Smell:
Camphoraceous, Musky, Floral, Pepperminty, Ethereal, Pungent, Putrid.
Odor Detection Threshold:
Examples: Hydrogen sulfide (0.0005 ppm), Methyl-mercaptan (0.002 ppm).
Some toxic substances are odorless at lethal concentrations.
Characteristics of Smell:
Odor blindness for single substances due to lack of appropriate receptor protein.
Behavioral and emotional influences of smell.
Transmission of Olfactory Signals:
From olfactory cells to glomeruli in the olfactory bulb, involving lateral inhibition.
Primitive, less old, and new olfactory systems with different path
MANAGEMENT OF ATRIOVENTRICULAR CONDUCTION BLOCK.pdfJim Jacob Roy
Cardiac conduction defects can occur due to various causes.
Atrioventricular conduction blocks ( AV blocks ) are classified into 3 types.
This document describes the acute management of AV block.
New Directions in Targeted Therapeutic Approaches for Older Adults With Mantl...i3 Health
i3 Health is pleased to make the speaker slides from this activity available for use as a non-accredited self-study or teaching resource.
This slide deck presented by Dr. Kami Maddocks, Professor-Clinical in the Division of Hematology and
Associate Division Director for Ambulatory Operations
The Ohio State University Comprehensive Cancer Center, will provide insight into new directions in targeted therapeutic approaches for older adults with mantle cell lymphoma.
STATEMENT OF NEED
Mantle cell lymphoma (MCL) is a rare, aggressive B-cell non-Hodgkin lymphoma (NHL) accounting for 5% to 7% of all lymphomas. Its prognosis ranges from indolent disease that does not require treatment for years to very aggressive disease, which is associated with poor survival (Silkenstedt et al, 2021). Typically, MCL is diagnosed at advanced stage and in older patients who cannot tolerate intensive therapy (NCCN, 2022). Although recent advances have slightly increased remission rates, recurrence and relapse remain very common, leading to a median overall survival between 3 and 6 years (LLS, 2021). Though there are several effective options, progress is still needed towards establishing an accepted frontline approach for MCL (Castellino et al, 2022). Treatment selection and management of MCL are complicated by the heterogeneity of prognosis, advanced age and comorbidities of patients, and lack of an established standard approach for treatment, making it vital that clinicians be familiar with the latest research and advances in this area. In this activity chaired by Michael Wang, MD, Professor in the Department of Lymphoma & Myeloma at MD Anderson Cancer Center, expert faculty will discuss prognostic factors informing treatment, the promising results of recent trials in new therapeutic approaches, and the implications of treatment resistance in therapeutic selection for MCL.
Target Audience
Hematology/oncology fellows, attending faculty, and other health care professionals involved in the treatment of patients with mantle cell lymphoma (MCL).
Learning Objectives
1.) Identify clinical and biological prognostic factors that can guide treatment decision making for older adults with MCL
2.) Evaluate emerging data on targeted therapeutic approaches for treatment-naive and relapsed/refractory MCL and their applicability to older adults
3.) Assess mechanisms of resistance to targeted therapies for MCL and their implications for treatment selection
Report Back from SGO 2024: What’s the Latest in Cervical Cancer?bkling
Are you curious about what’s new in cervical cancer research or unsure what the findings mean? Join Dr. Emily Ko, a gynecologic oncologist at Penn Medicine, to learn about the latest updates from the Society of Gynecologic Oncology (SGO) 2024 Annual Meeting on Women’s Cancer. Dr. Ko will discuss what the research presented at the conference means for you and answer your questions about the new developments.
Knee anatomy and clinical tests 2024.pdfvimalpl1234
This includes all relevant anatomy and clinical tests compiled from standard textbooks, Campbell,netter etc..It is comprehensive and best suited for orthopaedicians and orthopaedic residents.
Tom Selleck Health: A Comprehensive Look at the Iconic Actor’s Wellness Journeygreendigital
Tom Selleck, an enduring figure in Hollywood. has captivated audiences for decades with his rugged charm, iconic moustache. and memorable roles in television and film. From his breakout role as Thomas Magnum in Magnum P.I. to his current portrayal of Frank Reagan in Blue Bloods. Selleck's career has spanned over 50 years. But beyond his professional achievements. fans have often been curious about Tom Selleck Health. especially as he has aged in the public eye.
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Introduction
Many have been interested in Tom Selleck health. not only because of his enduring presence on screen but also because of the challenges. and lifestyle choices he has faced and made over the years. This article delves into the various aspects of Tom Selleck health. exploring his fitness regimen, diet, mental health. and the challenges he has encountered as he ages. We'll look at how he maintains his well-being. the health issues he has faced, and his approach to ageing .
Early Life and Career
Childhood and Athletic Beginnings
Tom Selleck was born on January 29, 1945, in Detroit, Michigan, and grew up in Sherman Oaks, California. From an early age, he was involved in sports, particularly basketball. which played a significant role in his physical development. His athletic pursuits continued into college. where he attended the University of Southern California (USC) on a basketball scholarship. This early involvement in sports laid a strong foundation for his physical health and disciplined lifestyle.
Transition to Acting
Selleck's transition from an athlete to an actor came with its physical demands. His first significant role in "Magnum P.I." required him to perform various stunts and maintain a fit appearance. This role, which he played from 1980 to 1988. necessitated a rigorous fitness routine to meet the show's demands. setting the stage for his long-term commitment to health and wellness.
Fitness Regimen
Workout Routine
Tom Selleck health and fitness regimen has evolved. adapting to his changing roles and age. During his "Magnum, P.I." days. Selleck's workouts were intense and focused on building and maintaining muscle mass. His routine included weightlifting, cardiovascular exercises. and specific training for the stunts he performed on the show.
Selleck adjusted his fitness routine as he aged to suit his body's needs. Today, his workouts focus on maintaining flexibility, strength, and cardiovascular health. He incorporates low-impact exercises such as swimming, walking, and light weightlifting. This balanced approach helps him stay fit without putting undue strain on his joints and muscles.
Importance of Flexibility and Mobility
In recent years, Selleck has emphasized the importance of flexibility and mobility in his fitness regimen. Understanding the natural decline in muscle mass and joint flexibility with age. he includes stretching and yoga in his routine. These practices help prevent injuries, improve posture, and maintain mobilit
Lung Cancer: Artificial Intelligence, Synergetics, Complex System Analysis, S...Oleg Kshivets
RESULTS: Overall life span (LS) was 2252.1±1742.5 days and cumulative 5-year survival (5YS) reached 73.2%, 10 years – 64.8%, 20 years – 42.5%. 513 LCP lived more than 5 years (LS=3124.6±1525.6 days), 148 LCP – more than 10 years (LS=5054.4±1504.1 days).199 LCP died because of LC (LS=562.7±374.5 days). 5YS of LCP after bi/lobectomies was significantly superior in comparison with LCP after pneumonectomies (78.1% vs.63.7%, P=0.00001 by log-rank test). AT significantly improved 5YS (66.3% vs. 34.8%) (P=0.00000 by log-rank test) only for LCP with N1-2. Cox modeling displayed that 5YS of LCP significantly depended on: phase transition (PT) early-invasive LC in terms of synergetics, PT N0—N12, cell ratio factors (ratio between cancer cells- CC and blood cells subpopulations), G1-3, histology, glucose, AT, blood cell circuit, prothrombin index, heparin tolerance, recalcification time (P=0.000-0.038). Neural networks, genetic algorithm selection and bootstrap simulation revealed relationships between 5YS and PT early-invasive LC (rank=1), PT N0—N12 (rank=2), thrombocytes/CC (3), erythrocytes/CC (4), eosinophils/CC (5), healthy cells/CC (6), lymphocytes/CC (7), segmented neutrophils/CC (8), stick neutrophils/CC (9), monocytes/CC (10); leucocytes/CC (11). Correct prediction of 5YS was 100% by neural networks computing (area under ROC curve=1.0; error=0.0).
CONCLUSIONS: 5YS of LCP after radical procedures significantly depended on: 1) PT early-invasive cancer; 2) PT N0--N12; 3) cell ratio factors; 4) blood cell circuit; 5) biochemical factors; 6) hemostasis system; 7) AT; 8) LC characteristics; 9) LC cell dynamics; 10) surgery type: lobectomy/pneumonectomy; 11) anthropometric data. Optimal diagnosis and treatment strategies for LC are: 1) screening and early detection of LC; 2) availability of experienced thoracic surgeons because of complexity of radical procedures; 3) aggressive en block surgery and adequate lymph node dissection for completeness; 4) precise prediction; 5) adjuvant chemoimmunoradiotherapy for LCP with unfavorable prognosis.
- Video recording of this lecture in English language: https://youtu.be/lK81BzxMqdo
- Video recording of this lecture in Arabic language: https://youtu.be/Ve4P0COk9OI
- Link to download the book free: https://nephrotube.blogspot.com/p/nephrotube-nephrology-books.html
- Link to NephroTube website: www.NephroTube.com
- Link to NephroTube social media accounts: https://nephrotube.blogspot.com/p/join-nephrotube-on-social-media.html
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NVBDCP.pptx Nation vector borne disease control programSapna Thakur
NVBDCP was launched in 2003-2004 . Vector-Borne Disease: Disease that results from an infection transmitted to humans and other animals by blood-feeding arthropods, such as mosquitoes, ticks, and fleas. Examples of vector-borne diseases include Dengue fever, West Nile Virus, Lyme disease, and malaria.
3. Genesis
cerebellum and its connecting pathways
proprioceptive sensory pathways
vestibular system
4. Cerebellar Dysfunction: Anatomy
Cerebellar parts Functions Signs
Posterior
(Flocculo-nodular lobe)
Archicerebellum
Body equilibrium
Eye movements
Eye movement disorders:
Nystagmus;
Vestibulo-ocular reflex
(VOR)
Postural and gait dysfunction
Midline
(Vermis; vermis of ant. lobe
pyramid , uvula and
paraflocculus)
Paleocerebellum
Input from spinal cord
Muscle tone
Axial stance and gait
Truncal & gait ataxia
Hemisphere
(middle portion of vermis,
cerebellar hemisphere)
Neocerebellum
Connected with Pons
and cortex through
thalalmus
Planning and initiation
of movements
Regulation of fine limb
movements
Limb ataxia:
Dysmetria,
Dysdiadochokinesis,
"intention" tremor
Dysarthria
Hypotonia
5. Cardinal features - Cerebellar pathology
– Stance and gait
– Poor regulation and coordination of skilled
movements (Dysmetria and dysdiadokinesia)
– Eye movement disturbances
– Altered Muscle tone (Hypotonia)
– Speech (Dysarthria)
7. Manifestations- Stance and gait
– Wide based stance & Gait
– Gait- staggering, irregular steps, lateral veering.
– Cerebellar gait -visible or more prominent
– Sudden turn, Abrupt stops , Tandem walking
– Ataxic sensory gait
• brisk leg movements
• legs placed far apart to correct instability
• steps of variable length
• need for carefully watching the ground.
• +ve Romberg's sign .
– Most of the autosomal recessive and dominant ataxias and with a
known genetic defect are characterized by the coexistence of
cerebellar and sensory ataxia
8. Limb coordination
• Asynergia- movements are broken into isolated subsequent steps , lack
easiness/ smoothness
• Dysdiadochokinesia- impaired REM
• Dysmetria. there is an abnormal excursion in movements and errors in
reaching a precise target
• Tests
– finger-to nose, the finger-chase tests for the upper limbs
– heel-to-knee and heel-to-tibia tests for the lower limbs.
• In coordination due to cerebellar disease is associated
– with abnormal speed of the movements
– to an excessive rebound phenomenon when an opposed motion is
suddenly released. ( due to a delay in contraction of the muscles, which
normally would arrest the flexion of the limb)
– Speed of initiating the movement is also slow and there is irregularity
in both acceleration and deceleration of movements
9. Tremor
• kinetic (intention) tremor
• static (postural) tremor may also occur.
• Related to hypotonia.
• In some cases of SCAs- myoclonus or chorea
may be superimpose on postural tremor.
10. Muscle tone
• Hypotonia is a typical cerebellar sign.
• Wider excursion of hands on shaking the arms.
• Obliteration of the space between the volar aspect of the wrist and
the deltoid.on a forced flexion of the arm at the elbow.
• In ataxic patient, the hypotonia is not a constant clinical sign.
– Present in FRDA1 patients, “pure” cerebellar syndromes- SCA6,
10, and 11 subtypes.
– In some other spinocerebellar disorders normal or increased
muscle tone may also be found - SCA3 or MSA.
11. Speech- Dysarthria
• Altered articulation of words
• Abnormal fluency of speech.
• Scanning Dysarthria
• Slurring
12. Ocular Motor Functions
• Smooth pursuit movements
• Saccades
• Certain clinical cerebellar syndromes might have characteristic
patterns
– FRDA1- fixation instability , square wave jerk, consistently
undershoot or overshoot the target during horizontal saccadic eye
movements (saccadic dysmetria)
– ABL -progressive paresis of the medial rectus muscles with
nystagmus of the adducting eye on lateral gaze was observed
– AR ataxias (some ) Oculomotor apraxia
– AD ataxias-
• Fragmentation of smooth pursuit movements,
• Saccadic dysmetria
• Nystagmus
• Saccadic slowing SCA1, SCA2, SCA3, SCA7, and SCA17
• ophthalmoplegia -SCA2 SCA1 and SCA3
16. Paraneoplastic-
cerebellardegenerations (PCD)
• associated with specific tumor
type antineuronal (anti purkinje
cell antibodies)
• late-onset ataxia and are
characterized by a sub acute
progressive course.
• Even if the cancer is found and
successfuly the disorder may well
not improve because cells are
irreversibly damaged.
• Functional outcome best in anti-
Ri,
• Survival worse with anti-Yo and
anti- Hu, better with anti Tr and
anti Ri
• Most common –
– Gynecological & breast
cancer
– Lung cancer
– Hodgkin's
• Small cell lung cancer
– anti-Hu, anti-Ri ( ANNA-2),
anti-VGCC,anti-
CRMP5/CV2* anti-
amphiphysin
• ovarian cancer
– anti-Yo ( PCA-1), anti-Ri,
anti-CRMP5/CV2
• breast cancer
– anti-Yo, anti-Ri
• Hodgkin’s disease
– anti-Tr and anti-mGluR1
• Testes-
– Anti Ma, Anti-Ta( Ma2)
• Colon-
– Anti-HU
17. Antigliadin antibodies
• Celiac disease or sprue is interesting cause of
ataxia
• Celiac disease is gluten sensitive enteropathy
• Cerebellar degeneration does not get better on
gluten free diet.
• Up to 40% of sporadic ataxias have anti-gliadin
antibodies
• Similar % in genetic ataxias
• Importance is not known.
• Bushara KO,Goebel SU, Shill H,GoldfarbLG,Hallett M (2001) Gluten sensitivityin sporadic and
hereditary cerebellarataxia.Ann Neurol 49:540–543
18. Genetic Ataxias
• Mendelian AR and AD ataxias have a higher frequency than other genetic ataxias.
• Prevalence – 1/50,000 - Friedreich’s ataxia (FRDA1)
• 1/100,000 - Ataxia Telangectasia (AT), dominant SCAs
• AR ataxias
– Multi-system disorders with extra-neural signs and symptoms - FRDA1 and AT
– Main mechanisms - loss of protein function,
• the control of energy output and oxidative stress -FRDA1, AVED, ABL,
possibly Cayman ataxia;
• the control of DNA maintenance and the cell cycle -AT, AOA1 and AOA2,
SCAN
• AD ataxias - restricted to the central nervous system.
– Mutant protein with a longer-than-normal poly glutamine stretch.
– Toxic gain-of-function of the aberrant protein
– Longer expansions-earlier onset, more severe disease in subsequent generations
– Diagnostic pathological feature-OPCA-(most common presentation of SCA+)
• AD episodic ataxias (EA)
– Point mutations in the potassium channel gene, KCNA1,- EA 1
– Point mutations in the CACNL1A4 gene - EA2
22. Spinocerebellar Ataxia (SCA)
Dominant SCA syndromes have many overlapping
signs: Difficult to distinguish on clinical grounds
Common features to all: Gait ataxia; Dysarthria
Features in some ataxias: Ocular D;
Extrapyramidal; Peripheral nerve; Intellectual D;
Seizures
Features with some predictive value for specific
gene defects
24. Relationship between ADCAs and SCAs
ADCA type SCA type
I -Cerebellar plus
(Pyramidal, Extra-pyramidal,
Ophthalmoplegia, & Dementia) 1,2,3,4,12,16,17, DRPLA
II Cerebellar + pigmentary
maculopathy 7
III pure cerebellar ± Mild
pyramidal signs 5,6,8,11,14,15,22
Ataxia and epilepsy 10
Early onset with mental retardation 13
25. SCA: Clinical Syndromes
•SCA 1: Hypermetric saccades; ++Tendon reflexes; Evoked motor
potentials Long conduction times
•SCA 2 Slowing saccads; Myoclonus or action tremor
•SCA 3/Machado-Joseph: Gaze-evoked nystagmus; Prominent
spasticity or neuropathy
•SCA 4: Cerebellar syndrome; Sensory neuropathy
•SCA 5: Pure cerebellar syndrome
•SCA 6: Pure cerebellar syndrome; -ve family history; Late onset > 50
•SCA 7: Retinal degeneration; Hearing loss; Onset in 1st decade
•SCA 8: Pure cerebellar syndrome
•SCA 10: Pure cerebellar syndrome ± Seizures
•SCA 11: Pure cerebellar syndrome
•SCA 12: Early arm tremor; Late dementia
•SCA 13: Early childhood onset; Mental retardation
•SCA 14: Ataxia; Myoclonus (with early onset)
26. Polyneuropathy in SCA
Axonal; Sensory or Sensory-Motor
SCA1: 42%; More with ↑ CAG repeats
SCA2: 80%
SCA3: 54%; More with fewer CAG repeats
SCA4: Sensory loss
SCA7: 0%
27. SPINOCEREBELLAR ATAXIA 1 ;SCA 1
SPINOCEREBELLAR ATORHY I
OLIVOPONTOCREBELLAR ATORPHY I; OPCA 1
OPCA I
MENZEL TYPE OPCA
CLINICAL SYNOPSIS
Neurological:
Miscellaneous:
Labs:
Gene Map Locus:6p 22-p23 CAG 40-83 ( N 6-40)
cerebellar ataxia
chorea
upper motor neuron signs
extensor planter, hyperreflexia
lower bulbar palsies
gaze paresis 50% , slow saccades 100 %
scanning and explosive speech
inco-ordination
onset third/fourth decade
earlier onset when inherited from father , anticipation
axonal neuropathy
atrophy of cerebellum, pons, olive,lower CN nuclei,
dorsal columns and spinocerebellar tracts
Reduced aspartic acid in brain
mutant protein Ataxin- 1, Intranuclear inclusions
28. SPINOCEREBELLAR ATAXIA 2; SCA 2
SPINOCEREBELLAR ATROPHY II
OLIVOPONTOCEREBELLAR ATROPHY, HOLGUIN TYPE
OLIVOPONTOCEREBELLAR ATROPHY 2
SPINOCEREBELLAR ATAXIA, CUBAN TYPE
CLINICAL SYNOPSIS
Neurological
Limbs
Miscellaneous
Labs
Gene Map Locus :12q23-24.1 CAG 34-59 ( N 14-31)
adult onset progressive cerebellar ataxia
palatal myoclonus , myokimia
slow saccadic eye movements 100%
dysarthria
ophthalmoparesis 40%, optic atrophy
pyramidal signs 20%
peripheral sensory loss, abolished tendon reflexes
dementia
extrapyramidal signs in Tunisian kindred
bladder dysfunction
no parkinsonian features
flexion contracture of legs
onset 2 - 65 yrs, 40% < 25 yrs, anticipation, may be
sporadic
involvement of cerebellum & inferior. olivary
nuc.,pons,spinal cord Ataxin - 2 , nuclear aggregates
31. SPINOCEREBELLAR ATAXIA 5; SCA5
CLINICAL SYNOPSIS
Neurological
Miscellaneous
Gene Map locus ; 11p12-q12
spinocerebellar ataxia
dysarthria
onset 10 -68 yrs
?descendents from paternal
grandparents of President
Abraham Lincoln
one family from NE France
anticipation probable
slow course
32. SPINOCEREBELLAR ATAXIA 6; SCA6
CLINICAL SYNOPSIS
Neurological
Miscellaneous
Labs
Gene Map Locus: 19p13.1-p13.2 CAG 21-31 ( N 4-20 )
spinocerebellar ataxia
frontal lobe signs, dysarthria
dementia
mild ophthalmoplegia, down beat & gaze evoked-
nystagmus
peripheral neuropathy
sense of imbalance on turning
seizures
other conditions associated with 19p13 are :
hemiplegic migraine, familial periodic cerebellar ataxia
onset ~30 if 25-27 repeats, ~40-50 if 21-24 repeats
sporadic 27%
cerebellar atrophy
α -1A voltage dependent calcium channel ( CACNL1A)
no inclusion bodies
37. SPINOCEREBELLAR ATAXIA 11: SCA 11
CLINICAL SYNOPSIS
Neurological
Miscellaneous
Labs
Gene map locus - 15q14-21.3
cerebellar ataxia 100%
horizontal > vertical nystagmus
(100%)
dysarthria (100%)
Limb ataxia (93%)
Hyper reflexia(100%)
no extrapyramidal ,weakness or
sensory signs
normal life expentancy
normal nerve conduction
isolated cerebellar atrophy
38. SPINOCEREBELLAR ATAXIA 12: SCA 12
CLINICAL SYNOPSIS
Neurological
Miscellaneous
Labs
Gene map locus 5q31-q33 CAG 66-93
( N-<29 )
Tremor arm & head
gait & limb ataxia
hyperreflexia
paucity of movements
eye movement abnormalities
dementia in oldest patients
onset 8-55 yr
German family
MRI cortical and cerebellar atrophy
protein phosphatease 2, R2B , brain
specific regulatory subunit of PP2A
involved in regulatory processes
39. SPINOCEREBELLAR ATAXIA 13: SCA 13
CLINICAL SYNOPSIS
Neurological
Miscellaneous
Labs
Gene map locus 19q13.3-
q13.4
Ataxia legs > Arms
dysarthria
nystagmus
motor dysfunction
poor running
inability to walk by 4-6th
decade
hyperreflexia
mental retardation
French family
7/8 females
onset early childhood
no anticipation
MRI pontocerebellar atrophy
40. SPINOCEREBELLAR ATAXIA 14: SCA 14
CLINICAL SYNOPSIS
Neurological
Miscellaneous
Labs
Gene map locus-19q13.4-qter
Ataxia legs >arms
axial myoclonus( younger in
onset<27 yr)
tremor in exteremities and
head ( younger onset)
hyperreflexia
Japanese family
? Anticipation
MRI Cerebellar atrophy
41. DENTATORUBRAL-PALLIDOLUYSIAN ATROPHY; DRPLA
MYOCLONIC EPILEPSY WITH CHOREOATHETOSIS
NAITO-OYANAGI DISEASE; NOD
ATROPHIN 1, INCLUDED
CLINICAL SYNOPSIS
Neurological:
Miscellaneous:
Labs:
Gene Map Locus: 12p13.31 CAG 49-75
(N<24)
Myoclonus
epilepsy ( longer repeats)
Dementia
Ataxia
Choreoathetosis
Onset usually in the 20s and death in the
40s
commaon in Japan
Combined degeneration of dentatorubral
and pallidoluysian systems
DRPLA protein , neuronal cytoplasm
42. EPISODIC ATAXIA, TYPE 1; EA1
PAROXYSMAL ATAXIA WITH NEUROMYOTONIA, HEREDITARY
EPISODIC ATAXIA WITH MYOKYMIA; EAM
ATAXIA, EPISODIC, WITH MYOKYMIA; AEM; AEMK
MYOKYMIA WITH PERIODIC ATAXIA
CLINICAL SYNOPSIS
Neurological
Miscellaneous
Labs
Treatment
Gene Map Locus: 12p13
Myokymia
Continuous muscle movement
Periodic ataxia
Continuous muscle movement
Periodic ataxia
Ataxic attacks provoked by abrupt postural
change, emotional stimulus, and caloric-vestibular
stimulation, startle
Onset in second decade
Hand posture resembling carpopedal spasm
Potassium voltage-gated channel gene mutation
Continuous spontaneous activity on EMG at rest
Muscle biopsy consistent with denervation, with
enlargement of muscle fiber
Phenytoin, not Acetazolamide
43. EPISODIC ATAXIA, TYPE 2; EA2
PERIODIC VESTIBULOCEREBELLAR CEREBELLOPATHY,
HEREDITARY PAROXYSMAL ATAXIA,
FAMILIAL PAROXYSMAL ATAXIA
ACETAZOLAMIDE-RESPONSIVE PAROXYSMAL CEREBELLARATAXIA; APCA
EPISODIC ATAXIA, NYSTAGMUS-ASSOCIATED CEREBELLAR ATAXIA
CLINICAL SYNOPSIS
Neurological
Miscellaneous
Labs
Treatment
Gene Map Locus: 19p13
Episodic ataxia
Cerebellar ataxia
Vertigo
Diplopia
Downbeat nystagmus
Ataxia precipitated by stress or
excitement, not by startle
attacks last 1/2 to 6 hrs.
point mutation alpha 1A calcium
voltage dependant channel
allelic with SCA6 & familial
hemiplegic migraine
Response to oral acetazolamide
44. CHOREOATHETOSIS/SPASTICITY, EPISODIC; CSE
CHOREOATHETOSIS, PAROXYSMAL, WITH EPISODIC ATAXIA
CHOREOATHETOSIS, KINESIGENIC, WITH EPISODIC ATAXIA AND SPASTICITY
DYSTONIA 9; DYT9
CLINICAL SYNOPSIS
Neurological
Miscellaneous
Treatment
Gene Map Locus: 1pNeuro :
Paroxysmal choreoathetosis.
Episodic ataxia.
Spasticity.
Increased tendon reflexes.
Pyramidal signs in legs.
Involuntary movements.
Dystonic limb posture.
Imbalance.
Dysarthria.
Perioral and leg paresthesias.
Headache.
Double vision.
Onset from 2 to 15 years.
Physical exercise, emotional
stress, lack of sleep, and alcohol
precipitate symptoms.
acetazolamide
45. Episodic Ataxias
Name Chromos
ome
Mutation Protein Clinical
EA type 1 12p Missense K-channel,
KCNA1
Interictal myokimia eyes, lips and fingers
PHT, Diamox
EA type 2 l9p Missense α-
component
the VDCA
CACNL1A4
Attacks of ataxia, dysarthria, N, V, Diplopia,
osciloscopia minutes to day. Interictal
nystagmus or mild ataxia. Provoked by
exercise and stress not startle. ½ pts have
headache. Diamox, 4 aminopyridinesame gene
as SCA -6 but nature of mutation differs
EA type3 Episodic vestibulo-cerebellar ataxia, Defective
smooth pursuit, gaze evoked nystagmus,
vertigo
EA type4 Vestibular ataxia, vertigo, tinnitis, interictal
myokymia - Diamox
EA with
Paroxysmal
choreoathetosi
s & Spasticity
1p Onset 2-15 yr
Attacks of ataxia, involuntary movements ,
dystonia or extremities , parasthethiasa and
headache 20 minutes 2/day-2/yr alc, fatigue,
stress, exercise- Diamox
EA type 5 2q CACNβ4 One family
46. FRIEDREICH’S ATAXIA
CLINICAL SYNOPSIS Gene Map Locus: 9q13 GAA 66->1700 ( N< 42)
Neurological: Cerebellar ataxia
Dysarthria
Nystagmus
Incoordined limb movements
Diminished or absent tendon reflexes
Babinski sign
Impaired position & vibratory sense
Hypoactive knee and ankle jerks
Cardiac : Hypertrophic cardiomyopathy ,CHF, Muscular subaortic stenosis
Skel : Pes cavus , Scoliosis, Hammer toe
Metabolic : Diabetes mellitus
Lab : Abnormal intranscription of protien FRATAXIN (resposible for Iron
efflux from mitochondria)
Abnormal- motor and sensory nerve conduction, EKG, ECHO,MRI
47. Evaluation
• History & Physical Examination
• Careful family history
• Standard laboratory including lipids and thyroid
• MRI Brain
• Autonomic testing ( Sphincter EMG)
• Genetic testing
• Toxic screen, Vitamin E
• Antibodies- paraneoplastic, antigliadin
48. Clinical History
• Accurate family history
• Look for anticipation- earlier onset , heavier clinical
expression in subsequent generations ( SCA 2,7)- gene
mutated parent is still asymptomatic or died before
developing clinical symptoms.
• Consanguity - recessive
• Age of onset – earlier in AR( exceptions-late onset
FRDA1, infantile cases of SCAs e.g. SCA2, SCA7)
• Origin of families-
– SCA3 - Portugal, Brazil, India, rare in Italy SA
– AVED – Southern Mediterranean
– AOA1 – Portugal, Japan
– Cayman Ataxia- Grand Cayman Island
49. Ataxia Rating Scales
• International Co-operative Ataxia Rating scale
(ICARS)
– Evaluation of efficacy of ataxia treatments
– Semi-quantitative 100 point scale
– 19 items divided in 4 sub-scores
• Posture and gait
• Kinetic functions
• Speech
• Ocular movements
• Trouillas et al. J International Cooperative Ataxia Rating Scale for pharmacological
assessment of the cerebellar syndrome. The Ataxia Neuropharmacology Committee of
the World Federation of Neurology J Neurol Sci. 1997 Feb 12;145(2):205-11
60. Resources
National Ataxia Foundation
2600 Fernbrook Lane, Suite 119
Minneapolis, MN 55447
Phone: 763-553-0020
Fax: 763-553-0167
E-mail: naf@ataxia.org
Web: www.ataxia.org
Spinocerebellar Ataxia: Making an Informed Choice about Genetic Testing
Web: depts.washington.edu/neurogen/AtaxiaBrochure99.pdf
WE MOVE (Worldwide Education and Awareness for Movement Disorders)
204 E 84th St
New York, NY 10024
Phone: 212-875-8312; 1-800-437-MOV2 , Fax: 212-875-8389
Email: wemove@wemove.org
Web: www.wemove.org
International Network of Ataxia Friends (INTERNAF)
Web: http://internaf.merseyside.org
62. Table 2. Autosomal Dominant Cerebellar Ataxias: Clinical
Features
Diseas
e
Name
Freque
ncy in
ADCA
Average Onset
(Range in
Years)
Average
Duration (Range in
Years)
Distinguishing Features
(All have gait ataxia)
SCA1
6%
(5-27)
4th decade
(<10 to >60)
15
(10-28)
Pyramidal signs,
peripheral neuropathy
SCA2
15%
(13-24)
3rd - 4th
decade
(<10 to >60)
10
(1-30)
Slow saccadic eye movement, peripheral neuropathy,
decreased DTR's, dementia
SCA3
21%
(11-36)
4th decade (10-
70)
10
(1-20)
Pyramidal and extrapyramidal signs; lid retraction,
nystagmus, decreased saccade velocity; amyotrophy
fasciculations, sensory loss
SCA4
Rare
4th - 5th decade
(19-59)
Decades
Sensory axonal
neuropathy
SCA5
Rare
3rd - 4th
decade
(10-68)
>25 Early onset, slow course
SCA6 15%
5th - 6th decade
(19-71)
>25 Sometimes episodic ataxia, very slow progression
SCA7 5%
3rd - 4th
decade
(1/2 - 60)
20
(1-45; early onset
correlates with short
duration)
Visual loss with retinopathy
SCA8 2-5% 39 (18-65) Normal lifespan Brisk DTRs and decreased vibration sense
SCA9 Category
not
assigned
SCA10
Rare 36 9 Occasional seizures
SCA11
Rare 30 (15-70) Normal lifespan Mild, remain ambulatory
SCA12
Rare 33 (8-55)
Early tremor,
late dementia
SCA13 Rare Childhood Unknown Mild mental retardation, short stature
DRPLA
Rare
(USA)
20%
(Japan)
8 - 20 or
40 - 60's
Early onset
correlates with
shorter duration
Chorea, seizures, dementia, myoclonus
EA1
Unknown 1st decade
(2-15)
Attenuates after 20
Myokymia; attacks last seconds to minutes; startle or
exercise induced; no vertigo
EA2
Unknown
3-52 Lifelong
Nystagmus; attacks last minutes to hours; posture change
induced; vertigo; later permanent ataxia
63. Table 3. Examples of Autosomal Recessive Hereditary
Ataxias: Molecular Genetics
Disease Name
Chromosome
Locus
Gen
e
Protein
Test
Availability
Friedreich ataxia
(FRDA)
9q13-q21
FRD
A1
Frataxin
Clinical
Ataxia-telangiectasia
(A-T)
11q22-q23 ATM PI3-kinase Clinical
Ataxia with vitamin E
deficiency
(AVED)
8q13
TTP
A
Alpha- tocopherol transfer
protein
Clinical
IOSCA 10q23-q24 ? ?
None
Marinesco- Sjögren ? ? ?
Spastic ataxia
(ARSACS)
13q11
SAC
S
SACSIN Research
64. Table 4. Examples of Autosomal Recessive Hereditary Ataxias: Clinical Features
Disease Name
Population
Frequency
Onset (Range
in Years)
Duration
(Years)
Distinguishing Features
Friedreich ataxia
(FRDA)
1-2/50,000
1st - 2nd
decade
(4-40)
10 - 30
Hyporeflexia,
Babinski responses,
sensory loss,
cardiomyopathy
Ataxia-
telangiectasia
(A-T)
1/40,000 to
1/100,000
1st decade 10 - 20y
Telangiectasia,
immune deficiency, cancer, chromosomal
instability, increased alpha-fetoprotein
Ataxia with
vitamin E
deficiency
(AVED)
Rare
2-52 years,
usually <20
Decades
Similar to FRDA,
head titubation (28%)
IOSCA
Rare
(Finland)
Infancy Decades
Peripheral neuropathy,
athetosis, optic atrophy, deafness,
ophthalmoplegia
Marinesco-
Sjögren
Rare Infancy Decades
Mental retardation,
cataract, hypotonia, myopathy
Spastic ataxia
(ARSACS)
Decades Childhood
Spasticity,
peripheral neuropathy, retinal striation
IOSCA = Infantile onset spinocerebellar ataxia
65. PATHOGENESIS
Accumulation of glutamate @ cleft leads to degeneration of
post synaptic neurons
Glutamate catabolism in brain glutamate in brain
causing neuronal destruction from over excitation and
degeneration
Plaitakis, et al. 1984
NMDA receptor mediated toxicity is most unifying
hypothesis
Role of mutant proteins & inclusion bodies is not known
66. PATHOGENESIS
Accumulation of glutamate @ cleft leads to degeneration of
post synaptic neurons
Glutamate catabolism in brain glutamate in brain
causing neuronal destruction from over excitation and
degeneration
Plaitakis, et al. 1984
NMDA receptor mediated toxicity is most unifying
hypothesis
Role of mutant proteins & inclusion bodies is not known
67. RECENT THEORIES
Botez’98
Drug cocktail L 5-HT(1000mg) , Amantidine (200mg) ,
Thiamine (50mg)
? Role - Remacemide ( NMDA recepter inhibiter in predominantly
cerebellum )
? Role - Gabapentin ( Neuroprotective )
? Role- Idebenone (Antioxidant )
Hypothesis of replacement and treatment in SCAs based on
↓ CSF 5-HIAA
NMDA- receptor mediated toxicity
↓ CSF Thiamine
Thiamine Rx ↑ 5-HIAA in pts with↓ CSF -thiamine &
5- HIAA
Cerebral vulnerability ↑ with ↑ EC glutamate in
thiamine def.
Pretreatment with NMDA recepter agonist MK-801
partially protects against thiamine induced brain
lesions.
75. Clinical Manifestations of
Cerebellar Dysfunctions
• Cerebellum- modulates motor functions
• Archicerebellum- ( flocculonodular node)
– Body equilibrium
– Eye movements
• Paleocerebellum( vermis of ant. lobe pyramid , uvula and
paraflocculus)
– Input from spinal cord
– Muscle tone
– Axial stance and gait
• Neocerebellum (middle portion of vermis, cerebellar
hemisphere)
– Connected with pons and cortex through thalalmus
– Planning and initiation of movements
– Regulation of fine limb movements
Editor's Notes
Incoordination of voluntary movements Clumsiness produced by dysfunction of the cerebellum or cerebellar pathways
impairment of joint position sense resulting from interruption of afferent nerve fibers in the peripheral nerves, posterior roots, or posterior columns of the spinal cord. The effect of these lesions is to deprive the patients of the knowledge of the position of their limbs
Movements are inaccurate and poorly controlled. The term ataxia includes several abnormalities of voluntary movements:
static (postural) tremor may also occur may cause arm instability and defective postural fixation at shoulder and elbow.
Hypotonia is a decrease in the normal resistance offered by muscles to passive manipulation When an affected limb is shaken flapping movements of the hands appear of wider excursion than normal.
Disorder may be a simple slowing of speech or may manifest as a slurring and scanning Dysarthria called because the words are broken into syllables. As the disease progresses, both slurring and slowness may occur and words might become difficult to understand
Oculomotor apraxia is a disorder of saccade initiation, and it has been described as an impaired ability to generate saccades on command, although induced saccades during spontaneous visual search and optokinetic stimulation are normal The term oculomotor apraxia has also been used to describe the inability to coordinate eyes-head movements when the head turns toward a lateral target and the head reaches the target before the eyes
Complex and includes all types of neurological pathological processes. Most patients presenting with ataxia will have sporadic disorder, there is increasing attention to genetic ataxias because of recent rapid advances.
spinocerebellar ataxia with axonal neuropathy SCAN
Incidence of dominant spinocerebellar and Fredreich triplet repeats among 361 ataxia families