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![Introduction
• Ataxia = from Greek- a- [lack of]+ taxia [order]
• Rate, rhythm and force of contraction of voluntary movements
• Disorganized, poorly coordinated, or clumsy movements
Traditionally used specifically for lesions involving
• Cerebellum or it’s pathways
• Proprioceptive sensory pathways](https://image.slidesharecdn.com/approachtoataxia-210914051954/75/Approach-to-Ataxia-2-2048.jpg)
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Approach to Ataxia
- 1. 1 PRESENTER- DR. VAIHBAVkr SOMVANSHI DM RESIDENT(NEUROLOGY) GMC,KOTA Approach to Ataxia
- 2. Introduction • Ataxia =from Greek- a- [lack of]+ taxia [order] • Rate, rhythm and force of contraction of voluntary movements • Disorganized, poorly coordinated, or clumsy movements Traditionally used specifically for lesions involving • Cerebellum or it’s pathways • Proprioceptive sensory pathways
- 3. Localisation • Cerebellum (mostcommon) • Sensory pathways (Sensory Ataxia)-posterior columns, dorsal root ganglia, peripheral nerves • Vestibular dysfunction
- 4. Localization of cerebellarlesions Gait ataxia Limb ataxia Dysarthria Titubation Action tremor 4 Anterior vermis Lateral hemispheres Posterior left hemisphere & vermis Ant. Vermis & associated deep nuclei Dentate nuclei, or cerebellar outflow to ventral thalamus
- 5. Localization of cerebellarlesions Palatal tremor Saccadic dysmetria Square wave jerks Gaze evoked nystagmus Higher cognitive changes 5 Dentate nucleus, Guillain Mollaret triangle Dorsal vermis Cerebellar outflow Flocculus & paraflocculus Lateral hemispheres
- 6.
- 7. Sensory Ataxia • Lossof distal joint, position sense • Absence of cerebellar signs such as dysarthria or nystagmus • Loss of tendon reflexes • Corrective effects of vision on sensory ataxia • Romberg sign
- 8. Vestibular Dysfunction • Vertigois prominent • Consistent fall to one side • Nystagmus • Limb ataxia is absent • Speech is normal • Joint position sense is normal
- 9. Approach to ataxicpatient Meticulous evaluation of History Age at Onset Course of disease Drug intake Family History Personal Social & Occupational information Distribution of ataxia History of other system illness Neurological evaluation Ancillary tests 9
- 10. History • Age atonset Childhood (congenital, metabolic, infectious, posterior fossa tumors, hereditary ataxias - more common) Adult (sporadic ataxias, hereditary ataxias) • Course of illness/progression Acute (metabolic/toxic, infectious, inflammatory, traumatic) Subacute (metabolic/toxic, infectious, inflammatory, paraneoplastic, tumor) Chronic (more likely genetic, degenerative, tumor, paraneoplastic) 10
- 11. • Drug intake –Phenytoin, barbiturates, lithium, immunosuppressants (methotrexate, cyclosporine), chemotherapy (fluorouracil, cytarabine) • Family history – Study at least 3 generations – Consanguinity – Ethnicity • Social/Occupational History – Alcohol and drug use, toxins (heavy metals, solvents, thallium), smoking (Vascular) History 11
- 12. Distribution of ataxia •Symmetric - Acquired, Hereditary, degenerative ataxias • Asymmetric- Vascular, Tumors, demyelinating, Infection, congenital causes Other system illness • Gastrointestinal symptoms- gluten ataxia • Mass lesion- paraneoplastic ataxias History 12
- 13. Children • Refusal towalk or with a wide-based, "drunken" gait. • Vertigo, dizziness and vomiting • Personality and behavioral changes. • Abnormal mental status • A history of head trauma ,neck trauma • Patients with a recent infection or vaccination • Previous similar episodes of acute ataxia. • Children with family members with ataxia 13
- 14. Examination Neurological examination • Ataxia(appendicular or axial) • Dysmetria • Dysdiadochokinesia • Rebound Phenomenon • Dysarthria • Tremor • Titubation and increased postural sway • Hypotonia • Nystagmus • Other system evaluation Breast Lump, mass per-abdomen etc. 14
- 15. Neuro-ophthalmologic evaluation inataxia Retinal pigmentosa Refsum disease, mitochondrial disorders Retinal/Macular degeneration SCA 7, aceruloplasminemia Optic atrophy/visual loss MS,FA Square wave jerks FA Occulomotor apraxia AT, AOA1, AOA2 Slow saccades Downbeat Nystagmus SCA2,SCA 7 SCA 6,EA2,anti GAD ataxia 15
- 16. Other Specific signs Focaland lateralized brainstem deficits(hemiparesis,facial palsy) Posterior circulation stroke, tumour, MS Paplidema, headache Posterior fossa tumours INO Posterior circulation stroke,MS Spasticity, UMN signs SCA 1,3,7,8 ,Strokes,tumour compressing brainstem Basal ganglia deficits SCA 1,2,12,17, MJD,MSA,Wilson Tremor SCA 12, 15, FAXTS 16
- 17. 17 Deafness Mitochondrial, superficialhimosiderosis Myoclonus Mitochondrial ,ceroid lipofuschinosis,SCA 7(early onset),SCA 14 Palatal myoclonus Alexander disease,SCA20 Cognitive decline Alcohol,MS,CJD,HIV,DRPLA,SCA12,13, superficial siderosis Psychiatric features SCA 12,17,27 Autonomic failure MSA,FXTAS Other Specific signs
- 18. Ataxia with Neuropathy •Friedreich ataxia • AOA2 • Fragile X syndrome • Vit E deficiency ataxia • Anti gliadin ataxia • SCA 2,3,4,12, 18,25,27 • Refsum disease 18
- 19. Ataxia with Dementia •Anti gliadin ataxia • FXTAS syndrme • SREAT • SCA 17, 19, 21, 2, 1, 6 • HIV/AIDS • Mitochondrial disease • Amylodosis 19
- 20. Ataxia with seizures •Anti GAD • Anti gliadin • Mitochondrial ataxia • Episodic ataxia 2, 4 • DRPLA • SCA 10, SCA 17 • CJD • SREAT 20
- 21. Investigations • Neuro imaging •Electro diagnostic tests • Ophthalmologic examination- Pigmentary retinopathy, macular degeneration, cataracts, Kayser-Fleischer rings
- 22. • Genetic tests •Metabolic – Thyroid function, vitamins B12, E, and B1, serum cholesterol & plasma lipoprotein profile, phytanic acid, toxicology screen(mercury, bismuth, lead, ethanol) • Immune function - Immunoglobulin levels, Antigliadin antibodies, GAD antibodies, paraneoplastic antibodies, Anti TPO.
- 23. Laboratory studies • Mitochondrial(Serum lactate and pyruvate) • Heavy metals,PBF for acanthocytes, VLCF, hexosaminidase A/B, alpha fetoprotein & immunoglobulins, serum ceruloplasmin & 24 hour urinary copper • CSF studies - Cell count, glucose and protein, oligoclonal bands, 14- 3-3 protein, GAD antibodies, paraneoplastic antibodies, lactate/pyruvate
- 24. • Diagnostic workflow Continuum movementdisorder 2019 pgno.161
- 25.
- 26. Genetic Testing Protocolof ataxias Spinocerebellar Ataxia Aut.Dominant Aut.Recessive Sporadic LOCA (>25) EOCA (<25) SCA 1 SCA 2 SAC 3 SCA 7 SCA 12 FRDA NO YES YES NO SCA 6 SCA 8 SCA 17 DRPLA YES NO Rare types of SCAs (ADCA) screening Investigation for other ARCA genes Level 20 Level 10 Level 30 features suggestive of SCA LOCA-Late onset cerebellar ataxia EOCA-Early onset cerebellar ataxia SCA27 SCA28 Age at Onset (Yrs) 10-30 >30 Variable SCA11 SCA14 SCA23 SCA5 SCA13 SCA14 SCA15 SCA28 26
- 27. Signs that DistinguishesSCA subtypes Benign course SCA 6 UMN signs SCA 1,7,8 and 3 Akinetic rigid syndrome SCA 3,2,17 & 12,21 Chorea SCA 2,1,3 Action tremor SCA 12,16 Slow saccades SCA 2 & 7 may be in 1,3 Downbeat nystagmus SCA 6 Hyporeflexia/Areflexia SCA 2,4,3 & 19,21 Vision loss SCA 7 Seizure SCA 10 Myoclonus SCA14 or SCA19 Cognitive impairment SCA2,14,19,21,23 27
- 28. Disease Additional featuresover Cerebellar Ataxia Distinguishable features Laboratory findings Sensory Axonal neuropathy MRI-spinal atrophy FA Pes cavus, Amyotrpohy, Extensor Plantar, Nystagmus Cardiomyopathy, DM GAA expansion in FXN Ataxia Vit E Def. Pes Cavus, Extensor Plantar, Head Tremor Retinitis Pigmentosa, Cardiomyopathy Low VitE MRI-Cerebellar Atrophy Infantile onset SCA Pes cavus, Amyotorphy, Ophthalmoplegia,Cognitive Impairment, Chorea Seizures,Hearing loss, Hypogonadism - MRI-Normal Abetalipop rotenemia Pes cavus, Amyotrophy Retinitis Pigmentosa, Lipid Malabsorption, Cardiomyopathy Low VitE, low lipoprotein, acanthocytes Clinical approach to ARCA MRI findings and Nerve conduction studies 28
- 29. Disease Additional featuresover Cerebellar Ataxia Distinguishable features Laboratory findings Ataxia with sensorimotor Axonal neuropathy MRI-Cerebellar Atrophy Late onset Tay sachs Amyotrophy, tremor, Myoclonus Prominent Extrapyramidal, Seizures,Psychiatric Impairment Hexoseaminidase levels- Ataxia telengiectasi a Occulomotor Apraxia, Amyotrophy,Tremor Myoclonus, Extrapyramidal, Babinski Sign Telengiectasia,Lymphoid cancer, Radiosensitivity,Immunodeficiency, DM High alpha-fetoprotein and low immunoglobin AT like disorders Occulomotor Apraxia, Extrapyramidal Radiosensitivity,Immunodeficiency low immunoglobin Ataxia with OA1 Occulomotor apraxia,Pes cavus, Amyotrophy, tremor, Extrapyramidal, cognitive impairment Scoliosis Low albumin, High Cholesterol Aprataxin gene Ataxia with OA2 Occulomotor Apraxia, Pes Cavus, amyotrophyTremors, Extrapyramidal, cognition Impairment Scoliosis High alpha-fetoprotein, High cholesterol Senataxin gene 29
- 30. Disease Additional featuresover Cerebellar Ataxia Distinguishable features Laboratory findings MRI-Spinal +Cerebellar Atrophy AR ataxia Charlevoix- Saguenay Pes Cavus, Amyotrophy, Spasticity, extensor Plantar, cogitive Impairment Chromosome 13 MRI-Cerebellar Atrophy + WMH Cerebrotendinou s xanthomatosis Pes Caus Amyotrophy, Spasticity, myoclonus, Parkinsonism Psychiatric Impairment,Tendon Xanthomas,Seizures,Cataract,Liver failure CYP27A1 30
- 31.
- 32.
- 33. Sporadic ataxias • Multiplesystem atrophy (MSA) • Toxins/metabolic • Paraneoplastic cerebellar degeneration • Immune-mediated ataxias (gluten, anti-GAD) • Infectious etiology 33
- 34. Antibody Condition Anti-Yo (Purkinjecell antobody type1) Breast and ovarian Ca Anti-Hu (Anti neuronal nuclear antibody type1) Small cell lung Ca (SCLC) Anti-Tr Hodgkin Lymphoma Anti-mGluR1 (metabotrpin glutamate receptor) Hodgkin Lymphoma Anti-CRMP5 (Collapsin receptor mediated protein)/Anti-CV2 SCLC Anti-ZIC4 (zinc finger protein) SCLC Paraneoplastic ataxia associated antibodies
- 35. Causes of sensoryataxia Polyneuropathy Paraneoplastic sensory neuronopathy Sjogren’s syndome Miller Fisher Syndrome Dysproteinemia Cisplatin Pyridoxine excess Acute sensory neuronopathy Chronic ataxic neuropathy Myelopathy Multiple sclerosis Tumour or cord compression Vascular malformation Vacuolar myelopathy Myeloneuropathy Freidriech’s Ataxia Vitamin B12 deficiency Vitamin E deficiency Tabes dorsalis Nitrous oxide 35
- 36. 36 Cerebral Sensory frontal Baseof support Wide base Looks down Wide base Velocity Variable Slow Very slow Initiation Normal Normal Hesitant Turns Unsteady Unstaedy Hesitant,multiple steps Postural instability + + +++++ Falls Late event More in night Frequent Heel shin Abnormal Abnormal,difficulty in point of initiation Normal Types of Ataxia
- 38. Management • Corrective measuresfor deficiencies – Vitamin E, Thiamine • Specific diet – Gluten free diet, ketogenic diet • Immunologic disorder – IVIG, Plasmapharesis • Miglustat for niemann pick disease • Riluzole – hereditary and degenerative ataxia and dysarthria • Varenicline – SCA3 • 4- aminopyridine, Acetazolamide – Episodic ataxia type 2 • Nicotinamide, deferiprone, idebenon – friedreich ataxia, mitochondrial ataxia • Rehabilitation, exercise help in SCA type 1 • Zinc supplementation and DBS also help in SCA 2 • Actimmune – IFN-γ analogue morbidity benefit for friedreich ataxia • Antisense oigonuceotide shown to knock down toxic protein level in SCA 2 and 3 mouse model 38
- 39. Case Scenario 55-year-old manpresented with progressive gait difficulty. He had initially noted difficulty walking downstairs, upstairs and running at the age of 47. His imbalance problems became progressively worse over the years, and he developed slurred speech, transient double vision while turning his head quickly, and loss of hand dexterity. He had frequent falls and needed to use a walker. He had an extensive family history of cerebellar ataxia, affecting his mother and brother. On examination, he had slurred speech and slow saccadic eye movements without nystagmus or hypermetric or hypometric saccades. He had dysmetria on finger-nose-finger tests and overshoot in finger chase tests. He also had impaired rapid alternating movements with absent reflexes in upper limb and hyporelexia in lower limb. He had a hypomimic facial expression and bradykinesia left side with retropusion test positive. His gait showed variable stride length and was wide based. 39
- 40.
- 41. Genetic tests -38 repeats CAG expansions of the ATXN2 gene (normal <32), Diagnosed as SCA 2 The patient treated with riluzole 50 mg 2 times a day which provided modest benefits for his speech. Physical therapy helped with his balance. Carbidopa/levodopa 25 mg/100 mg, 3 times a day, improved his parkinsonism by increasing the speed of her movements. 41
- 42. Conclusion An approach toataxia is based on knowledge of its symptoms and causes Knowledge of differentiating clinical features takes clinicians closer to the etiological diagnosis which help in investigational decisions. Treatable causes must be identified and ruled out Genetic testing is prudent for providing better insight into the management. • On going clinical trials for management of hereditary and degenerative ataxias will help in better morbidity outcome of these diseases. 42
- 44. • Bradley’s Neurologyin clinical Practice,eighth edition • Handbook of Clinical Neurology, Vol. 103 (3rd series), Ataxic Disorders • http://www.ataxia.org -National Ataxia Foundation web site • http://www.ncbi.nlm.nih.gov/books/NBK1138/ Detailed information about ataxias • http://www.clinicaltrials.gov –clinical trials information • Pubmed-with the searchterms “spinocerebellar ataxia”,“Friedreich’s ataxia”, “sporadic ataxia”,“sensory ataxia”, “approach to ataxia”, “ataxiadiagnosis” • The Cochrane Library • Continuum movement disorder 2016 • Continuum movement disorder 2019 • prabhakar_sudesh_singh_gagandeep_eds_differential_diagnosis chapter 22 pg.no.251 References 44
- 45. Genotype-Phenotype correlations inSCA2 Higher repeats are associated with earlier onset Homozygous expansion- no increase in severity Allelic variations of RAI 1 and CACNA1A influences age at onset Disease duration X CAG length affects occurrence of slow saccades, Fasciculation, Amyotrophy, Areflexia and Vibration senses Small disease alleles (32-37): Postural Tremors and Parkinsonism, late onset disease Medium Size alleles (38-44) : Ataxia, areflexia and slowing of saccades Large Size Alleles (>45) : Onset <20 years, Chorea and dementia Higher Size Alleles (>91) : Ataxia, Dystonia, Myoclonus, Cardiac failure, optic atrophy
- 46. Genotype-Phenotype correlations in SCA1 Higherrepeats are associated with earlier onset and severe disease Homozygous expansion- no increase in severity Small disease alleles (39-44) interrupted: Mild Phenotype, Ataxic/non ataxic features Medium Size alleles (39-50) Pure CAG: Ataxia and Pyramidal syndrome Large Size Alleles (>50) Pure CAG: Ataxia and Pyramidal syndrome & Amytrophic Lateral sclerosis Higher Size Alleles (>91): Juvenile disease
- 47. Genotype-Phenotype correlations in SCA3 Earlieronset with Higher repeats and inverse correlation Homozygous expansion- confers increasing severity Small disease alleles (52-73): Axonal Neuropathy and Parkinsonism (Type-III MJD) Medium Size alleles (73-80) : Ataxia and Diplopia (Type-II MJD) Large Size Alleles (80-86) : Ataxia, Dystonia and spasticity (Type-I MJD) Higher Size Alleles (>86) : Rare cases predominant Dystonia (Type-IV)
- 48. Genotype-Phenotype correlations in SCA7 Earlieronset with higher repeats and anticipation Greater expandability during transmission of alleles Recurrent denovo expansions Small disease alleles (36-41): Cerebellar ataxia without Retinal involvement Medium Size alleles (42-49) : Ataxia preceedes Vision diminution Large Size Alleles (49-60) : Vision loss preceedes Ataxia Higher Size Alleles (>80) : Juvenile Onset Extreme High Length Alleles : Infantile Onset, Developmental failure, Multisystem involvement (>200)
Editor's Notes
- #6 Red nucleus Infeior olivary nucleus Contralateral detate nuceus
- #7 Organ of 3
- #8 30 seconds
- #9 Peripheral vestibular – fatiguable nystagmus- vertigo better with affected ear up while sleeping Central vestibular – fast component away from the eccentric side
- #10 Symmetrical/ unilateral
- #12 SCA 12 north india 1,2,3,7 SCA 6 japanes
- #13 Congenital – Arnold chiari malformation
- #15 Intention, action Cerebellar Hypotonia aka gamma spasticity (preserved reflexes) Gamma alpha coordination failure Occular flutter – to and froth saccading movement like square wave jerk without pause Opsoclonus – chaotic continuous multidirectional rapid eye movement Suare wave jerk- opposite direction saccadic eye movement more than 0.3degree with no movement in between ( >10 movement – abnormal)
- #16 Ataxia with oculomotor apraxia
- #23 Repeat sequencing WGS Anti GQ1 ab - MFS
- #24 Murcury, bismuth, lead Low CSF glucose – glucose transporter type 1 deficiency AFP – AOA 1, 2
- #25 AD = autosomal dominant; AR = autosomal recessive; FXTAS = fragile X tremor-ataxia syndrome; GAD = glutamic acid decarboxylase; ILOCA = idiopathic late-onset cerebellar ataxia; MRI = magnetic resonance imaging; MSA = multiple system atrophy; REM = rapid eye movement; SCA = spinocerebellar ataxia.
- #26 HD, Hodgkin's disease; OPCA, olivopontocerebellar atrophy; RD, registered dietitions; DRPLA, dentatorubral-pallidoluysian atrophy; ARSAS, autosomal recessive spastic ataxia of Charlevoix Saguenay; CTX, cerebrotendinous xanthomatosis; MIRAS, mitochondrial recessive ataxia syndrome. MSS – marinesco sjogren syndrome
- #27 Genetic analyses should be directed according to the frequency of genetic subtypes in the relevant ethnic background (figure 1) and with regard to clinical features.
- #32 Axial T2-weighted MRI sequence shows the hot cross bun sign - multiple system atrophy selective loss of myelinated transverse pontocerebellar fibers and neurons in the pontine raphe with preservation of the pontine tegmentum and corticospinal tracts. May be seen in SCA 2 SCA 3 Vcjd HIV related PML Axial T2-weighted brain MRI demonstrates hyperintensities in the bilateral inferior olivary nuclei - POLG ataxia. SANDO syndrome – POLG mutation - sensory ataxia neuropathy dysarthria ophthalamoplegia Sagittal T1-weighted brain MRI spinal cord atrophy but no cerebellar atrophy - Friedreich ataxia (GRE) axial brain MRI show hypointensity surrounding the brainstem, cerebellum, and spinal cord - superficial siderosis. Fragile X tremor-ataxia syndrome. Axial T2- weighted MRI symmetric increased signal within the MCP.
- #33 axial T2-weighted MRI slices demonstrate linear hypointensity in the pons. autosomal recessive spastic ataxia of Charlevoix-Saguenay showing degeneration of the corticospinal tract Joubert syndrome. delayed milestones, a prominent forehead and low-set ears, and cerebellar ataxia, hypotonia, and hyperreflexia, showing dysgenesis of the isthmus (the part of the brainstem between the pons and inferior colliculus), thick superior cerebellar peduncles, and hypoplasia of the vermis- molar tooth sign. Sign also seen – hepatic fibrosis, nephronopthisis, cogan’s syndrome, pontine tegmental cap dysplasia
- #35 Anti-Ri
- #39 Loss of frataxin function in mitochondria leads to iron-sulfur cluster deficits, impaired oxidation, and iron accumulation. Nicotinamide has been shown to increase frataxin but no clinical benefit iron chelator deferiprone and the antioxidant idebenone are unclear on long-term benefit with side effect of heart muscle injury. Idebanon – Co-enzyme Q analogue
- #40 Brain MRI showed pontocerebellar atrophy Axial(SPECT) - SCA 2 shows a marked symmetrical reduction of dopamine transporter binding in the caudate nucleus and putamen. 18-FDG PET - SCA2. Representative sagittal (top), coronal (mid) and axial (bottom) images of 18F-fluorodeoxyglucose uptake show diffusely decreased hypometabolism in the cerebellar cortex and dentate nuclei (mid and bottom images). Note in the SCA2 patients, the decreased tracer uptake in the basis pontis and medulla oblongata as well
- #41 Dorsal spooning Pseudoathetosis