Feature Story Overview of Adult Onset Cerebellar By Pravin Khemani, MD

he are clinically heterogenous disorders correlated with disease than others. For example: caused by pathological processes affecting the • Postural dizziness, erectile dysfunction, urinary symptoms, and cerebellar pathways resulting in and dream-enactment behavior (suspicious for Rapid impaired coordination. The cerebellum’s main func- eye movement behavior disorder or REMBD): Multiple tionT is to integrate information relayed to it and facilitate System Atrophy-C (MSA-C) the execution of precise movements. Lesions of the cerebel- • Profound cognitive and behavioral changes: sporadic lum and its connections can result in breakdown and inco- Creutzfeldt-Jakob disease (CJD); paraneoplastic, infec- ordination of movement. tious, and immune-mediated limbic encephalitides Other neurological symptoms, when corroborated by What processes can cause ataxia? examination findings, may help with the diagnosis. The pathophysiology of cerebellar ataxias is as diverse as Family history of ataxia, when present, is very helpful for the various neurological and systemic diseases affecting diagnosis of genetic ataxias. However, when the family his- the cerebellum. Broadly classifying ataxias into genetic and tory is absent or unknown, this does not exclude a genetic non-genetic conditions is a first step in discovering their cause. Usual patterns of inheritance are autosomal domi- underlying mechanism. Non-genetic ataxias are caused by nant (AD) or recessive (AR) and X- linked. Consanguinity acquired conditions, sporadic neurodegenerative disorders, between parents should alert to an autosomal recessive or from unknown processes in which case the descriptive disorder. term idiopathic late-onset cerebellar ataxia1 (ILOCA) is used Common risk factors for cerebellar damage include: to describe the disorder. • frequent and excessive alcohol consumption; exposure to toxins such as mercury; use of medications like phe- What are common cerebellar symptoms? nytoin, lithium, and chemotherapeutic agents Difficulties with gait and balance are the most common • HIV, hepatic cirrhosis, (MS), and auto- symptoms, often described as “losing balance,” “staggering,” immune diseases “walking like a drunk,” “cannot walk a straight line,” etc. • gastric-bypass procedures and malabsorption states Other complaints include dizziness, blurred vision, slurred causing deficiency of vitamins E and B1. speech, difficulty with swallowing, clumsiness, sloppy hand- writing, poor fine motor skills, and . What does variability in rate or progression indicate? What is involved in the evaluation of Rate of progression of ataxic symptoms can be associated an ataxic patient? with specific causes of ataxia.3 As with all neurological disorders, a detailed history and Acute and abrupt onset is associated with strokes and thorough examination are prerequisites for an accurate structural lesions. Rapid progression in hours or days diagnosis and set the stage for the diagnostic investigation. is associated with infectious or parainfectious cerebellitis; Motor and non-motor symptoms, family history, acquired immune-mediated disorders such as Miller-Fisher syndrome risk factors (exposure to toxins and certain general medical (MF); acute toxin exposure; rapid metabolic derangement; conditions), and tempo of progression are key elements of or multiple sclerosis (MS). the history.2 Progression over weeks to months is associated with Cerebellar symptoms (see above) point to an ataxic disor- paraneoplastic disorders; anti-glutamic acid decarboxylase der, while some non-cerebellar symptoms are more tightly (GAD)-antibody syndrome; steroidresponsive encephalopa-

38 Practical March/April 2013 Feature Story

thy and ataxia (SREAT or Hashimoto’s encephalopathy); • Visual loss: MS; ataxia with vitamin E deficiency (AVED); gluten ataxia in Celiac disease (GA); vitamin deficiency states SCA7; mitochondrial disorders. [e.g. ataxia with vitamin E deficiency or AVED, B1 (thiamine) • Neuromuscular deficits: mitochondrial disorders. deficiency]; general medical conditionsHeadline such as hepatic • Telangiectasias: AT. encephalopathy; infections (HIV, CJD); MS; or sensory poly- • Achilles xanthomas and early cataracts: neuropathy and ganglionopathy (SPN and SG). Cerebrotendinous xanthomatosis, CTX. Chronic and indolent progression over months to years is most frequently associated with genetic ataxias; toxins (pri- What diagnostic tests are marily alcohol); MS; storage disorders (lipid, lysosomal, per- recommended for ataxia evaluation?1,2 oxisomal); sporadic neurodegenerative disorders (MSA-C); Brain MRI is indispensable. It may reveal: ILOCA; SPN and SG; atypical parkinsonian conditions. such Deck • Structural lesions and strokes. as Progressive supranucleary palsy (PSP); or Neurosyphilis • Atrophy of the cerebellum and : chronic pro- (NS). cesses such as genetic ataxias. byline Rates of progression vary in individuals. All possible etiolo- • Abnormal signal and atrophy of the : gies should be considered when the clinical course is not Wilson’s disease; HD; mitochondrial disorders; NAC. firmly established. These include: • Putaminal atrophy and cruciform hyperintensity in the • Cerebellar signs: , saccadic , (“hot-cross bun” sign): MSA-C. impairedext text cancellation text text text of vestibulo-ocular text text text text reflex, text dys text- • Middle cerebellar peduncle lesions: FXTAS. arthria,text limb text ataxia,text text titubation, text text dyssenergia,text text text impaired text text • White matter abnormalities: MS; adult-onset checktext on text rebound text text testing, text textend-intention text text text tremor, text widetext leukodystrophies (Alexander disease, AD; stance,text and text difficulty text text with text tandemtext text stance text text and text gait. text Adrenoleukodystrophy, ALD). textT• Extracerebellartext text text text signs text and text related text textdiseases: text 3,4text Orthostatic • Diffusion-weighted abnormalities (“cortical ribboning”) hypotension, dysphonia, , pyramidal signs, and and symmetric thalamic changes (“pulvinar” sign): CJD parkinsonism: MSA-C (the most common non-genetic Spinal cord MRI is suggested for myelopathic signs. degenerative ataxia). • Severe cord atrophy: FA; Alexander disease • Dystonia, Parkinsonism: Several SCAs; DRPLA; Wilson’s Additionally, serum testing may be indicated and is guid- disease and Neuroacanthocytosis (NAC) in a younger ed by the clinical evaluation and imaging: cohort. • First tier: blood chemistries; renal and liver function • Action tremor, dysexecutive syndrome, neuropathy, tests; ammonia; complete blood counts with differen- Parkinsonism: Fragile-X tremor ataxia syndrome tial (CBC diff); erythrocyte sedimentation rates (ESR); (FXTAS). Antinuclear antibodies (ANA); thyroid and vitamin • : Huntington disease, HD; dentatorubropallido- levels (B12, B1, E, B6, A); folate; glucose tolerance test; luysian atrophy, DRPLA; SCA 17; Ataxia telangiectasia, methylmalonic acid; infectious serologies (HIV antibody, AT; SCAs.1,2,3 Lyme antibody, RPR); Serum protein electrophoresis • Myoclonus and cognitive impairment: hepatic encepha- with immunofixatoin (SPEP with IFE). lopathy; CJD; anti-GAD syndrome; POLG (polymerase • Second tier (tests for rare ataxias and potentially treat- g) mutation. able conditions, to be ordered if 1st tier testing is incon- • Pyramidal signs, sensory loss: Strokes; acquired and clusive): creatine kinase; lactate; pyruvate; α-fetoprotein genetic myelopathies; hereditary spastic parapareses; (elevated in AT and AOA 2); fasting lipid profile; spinocerebellar ataxias (SCAs); Friedrich’s ataxia (FA); paraneoplastic antibodies (Hu, Yo, Ri, Ma, TA, CARP8, MS; NS. CV2, Tr, LEMS, MGLUR1, CRMP5, GQ1b, amphiphysin, • Sensory loss, hyporeflexia: AR ataxias; SPN and SG (“sen- PCA-2, NMDA, VGKC, ganglionic acetylcholine receptor sory ataxia”); GA; MF; AVED; NS. antibodies); anti GAD65 antibodies; SSA, SSB antibodies • Cognitive and psychiatric symptoms: CJD; Wernicke- (Sjögren’s antibodies); antigliadin antibodies (IgA and Korsakoff syndrome; SCA 17; late-stage AD ataxias; AR IgG); serum iron studies; alkaline phosphatase; thyro- adult-onset inborn errors of metabolism; leukodystro- peroxidase (TPO) antibodies; 24 hour urine copper and phies; NS; Whipple’s disease. zinc; serum copper and ceruloplasmin; urine heavy met- • Eye-movement abnormalities: MS; ataxias with oculomo- als; Human T-Cell lymphotropic virus I, II; T. Whippelei tor apraxia 1 and 2 (AOA1, AOA2); SCA 2; Whipple’s PCR; cholestanol levels (if CTX is suspected) disease; Ataxia telangiectasia, AT; MF; PSP (impaired • Third tier (rarer genetic conditions typically seen in a vertical saccades). younger cohort with ataxia and other symptoms such

March/April 2013 Practical Neurology 39 Feature Story

as dystonia, peripheral neuropathy, visceral involvement pharmacologic agents include acetazolamide is used for and cognitive impairment): peripheral blood smear EA2, SCA 6 and varenicline (Chantix®) for SCA 3.7 Bile acid for acanthocytes (for NAC); lysosomal screen; plasma replacement may be tried for CTX. amino acids; urine organic acids; serum ketones; fasting Common sense measures include elimination of toxins; very long chain fatty acids (for ALD) correction of deficiency states; and, treatment of medical Cerebrospinal fluid studies are obtained for paraneoplas- disorders causing ataxia. tic, immune-mediated, infectious, and inflammatory disor- Non-specific pharmacological agents of potential benefit ders: protein; glucose; CBC diff; cultures; IgG synthesis, index, include amantadine, alpha-lipoic acid, buspirone, branched- rate; oligoclonal bands; cytology; lactate; 14-3-3 protein; chain amino acids, creatine, coenzyme Q10, vitamin E, paraneoplastic antibodies; viral encephalitis panel; VDRL. physostigmine, riluzole, and selective serotonin reuptake CT or PET scan of the body may be indicated to look inhibitors. Cerebellar tremor may improve with primidone for occult malignancy. Additional tests that may be and antiepileptics; oscillopsia with memantine and GABA helpful in certain settings include EEG (helpful in CJD), agonists; and spasticity with central anti-spasticity drugs. Electromyogram and nerve conduction studies, autonomic A multidisciplinary approach is necessary in MSA-C, due a studies, or sleep study (to look for REMBD). Rarely, nerve multitude of progressive motor and non-motor symptoms. and muscle biopsies are used for suspected mitochondrial Rehabilitative therapies should be offered to all patients ataxias or brain biopsy for suspected leukodystrophies. with ataxia. Continuous exercise programs have shown posi- Other rarely indicated tests include magnetic resonance tive results.8 spectroscopy of the brain, dopamine transporter SPECT (DaT) scan (abnormal in MSA-C), or genetic tests. Summary The literature offers a detailed discussion of genetic atax- The diagnostic approach to adult onset ataxias should be ias.6,7 The patient should be appropriately counseled about systematic and guided by the history and examination. the implications and costs of genetic testing before it is Non-genetic ataxias may involve an extensive and expensive ordered. Testing may reveal: evaluation that may be done in a tiered fashion. MSA-C is • AD mutations: SCAs (most common worldwide is SCA the most common sporadic ataxia. ILOCA is a diagnosis of 3 or Machado-Joseph disease), DRPLA, and the rare epi- exclusion. sodic ataxias (EA 1, EA 2). A positive familial history signals a genetic disorder. • AR mutations: have usual age of onset <20 years but Patients undergoing genetic tests should be appropriately later onset FA, AT, AOA 2 have been reported; POLG counseled. mutations. Effective management of ataxic disorders requires a mul- • X-linked mutation (premutation in the FMR1 gene): tidisciplinary approach involving disease-specific and symp- FXTAS. tomatic drug treatment as well as rehabilitative measures. n • Mitochondrial DNA mutations. Specialized gene tests for inborn errors of metabolism, Reprinted with permission from “Broca’s Area,” the newslet- leukodystrophies, and storage disorders should be ordered ter of the Texas Neurological Society. if the rest of the evaluation raises suspicion for these rare conditions. Dr. Khemani is Assistant Professor, Clinical Center for Movement Disorders, Department of Neurology and What if no cause is identified Neurotherapeutics at University of Texas Southwestern after extensive testing? Medical Center in Dallas, Texas A large number of sporadic ataxias do not seem to have an identifiable etiology. When followed over time about one- 1. Fogel, B.L. and S. Perlman, An approach to the patient with late-onset cerebellar ataxia. Nature Clinical Practice Neurol- ogy, 2006. 2(11): p. 629-635. third of ILOCAs may evolve to MSA-C1 Unidentified genetic 2. van Gaalen, J. and B.P.C. van de Warrenburg, A practical approach to late-onset cerebellar ataxia: putting the disorder mutations may account for the rest of these ataxias. with lack of order into order. Practical Neurology, 2012. 12(1): p. 14-24. 3. Subramony, S.H., Approach to ataxic diseases. Handbook of Clinical Neurology, 2012. 103: p. 127-134. 4. Manto, M. and D. Marmolino, Cerebellar ataxias. Current Opinion in Neurology, 2009. 22(4): p. 419-429. How are ataxias treated? 5. Schöls, L., et al., Autosomal dominant cerebellar ataxias: clinical features, genetics, and pathogenesis. The Lancet Specific interventions for acquired ataxias include steroids Neurology, 2004. 3(5): p. 291-304. 6. Fogel, B.L. and S. Perlman, Clinical features and molecular genetics of autosomal recessive cerebellar ataxias. The Lancet and other immunomodulating therapies for SREAT, para- Neurology, 2007. 6(3): p. 245-257. neoplastic disorders, and other immunological disorders. 7. Zesiewicz, T.A., et al., A randomized trial of varenicline (Chantix) for the treatment of type 3. Neurology, 2012. 78(8): p. 545-550. When an underlying malignancy is detected, it must be 8. Ilg, W., et al., Intensive coordinative training improves motor performance in degenerative cerebellar disease. Neurol- treated. Gluten-free diets are indicated for GA. Specific ogy, 2009. 73(22): p. 1823-30.

40 Practical Neurology March/April 2013