Possible causes of Ataxia: 🙂 This is a ‘long read... - Ataxia UK

Ataxia UK

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Possible causes of Ataxia

wobblybee
wobblybee

🙂 This is a ‘long read’ and may be difficult to interpret, but never the less it’s interesting.

What processes can cause ataxia?

The pathophysiology of cerebellar ataxias is as diverse as the various neurological and systemic diseases affecting the cerebellum. Broadly classifying ataxias into genetic and non-genetic conditions is a first step in discovering their underlying mechanism. Non-genetic ataxias are caused by acquired conditions, sporadic neurodegenerative disorders, or from unknown processes in which case the descriptive term idiopathic late-onset cerebellar ataxia1 (ILOCA) is used to describe the disorder.

What are common cerebellar symptoms?

Difficulties with gait and balance are the most common symptoms, often described as “losing balance,” “staggering,” “walking like a drunk,” “cannot walk a straight line,” etc. Other complaints include dizziness, blurred vision, slurred speech, difficulty with swallowing, clumsiness, sloppy handwriting, poor fine motor skills, and tremor.

What is involved in the evaluation of an ataxic patient?

As with all neurological disorders, a detailed history and thorough examination are prerequisites for an accurate diagnosis and set the stage for the diagnostic investigation. Motor and non-motor symptoms, family history, acquired risk factors (exposure to toxins and certain general medical conditions), and tempo of progression are key elements of the history.2

Cerebellar symptoms (see above) point to an ataxic disorder, while some non-cerebellar symptoms are more tightly correlated with disease than others. For example:

Postural dizziness, erectile dysfunction, urinary symptoms, and dream-enactment behavior (suspicious for Rapid eye movement behavior disorder or REMBD): Multiple System Atrophy-C (MSA-C)

Profound cognitive and behavioral changes: sporadic Creutzfeldt-Jakob disease (CJD); paraneoplastic, infectious, and immune-mediated limbic encephalitides

Other neurological symptoms, when corroborated by examination findings, may help with the diagnosis.

Family history of ataxia, when present, is very helpful for diagnosis of genetic ataxias. However, when the family history is absent or unknown, this does not exclude a genetic cause. Usual patterns of inheritance are autosomal dominant (AD) or recessive (AR) and X- linked. Consanguinity between parents should alert to an autosomal recessive disorder.

Common risk factors for cerebellar damage include:

frequent and excessive alcohol consumption; exposure to toxins such as mercury; use of medications like phenytoin, lithium, and chemotherapeutic agents

HIV, hepatic cirrhosis, multiple sclerosis (MS), and autoimmune diseases

gastric-bypass procedures and malabsorption states causing deficiency of vitamins E and B1.

What does variability in rate or progression indicate?

Rate of progression of ataxic symptoms can be associated with specific causes of ataxia.3

Acute and abrupt onset is associated with strokes and structural brain lesions. Rapid progression in hours or days is associated with infectious or parainfectious cerebellitis; immune-mediated disorders such as Miller-Fisher syndrome (MF); acute toxin exposure; rapid metabolic derangement; or multiple sclerosis (MS).

Progression over weeks to months is associated with paraneoplastic disorders; anti-glutamic acid decarboxylase (GAD)-antibody syndrome; steroidresponsive encephalopa thy and ataxia (SREAT or Hashimoto’s encephalopathy); gluten ataxia in Celiac disease (GA); vitamin deficiency states [e.g. ataxia with vitamin E deficiency or AVED, B1 (thiamine) deficiency]; general medical conditions such as hepatic encephalopathy; infections (HIV, CJD); MS; or sensory polyneuropathy and ganglionopathy (SPN and SG).

Chronic and indolent progression over months to years is most frequently associated with genetic ataxias; toxins (primarily alcohol); MS; storage disorders (lipid, lysosomal, peroxisomal); sporadic neurodegenerative disorders (MSA-C); ILOCA; SPN and SG; or Neurosyphilis (NS).

Rates of progression vary in individuals. All possible etiologies should be considered when the clinical course is not firmly established. These include:

Cerebellar signs: Nystagmas, saccadic dysmetria, impaired cancellation of vestibulo-ocular reflex, dystarthria, limb ataxia, titubation, dyssenergia, impaired check on rebound testing, end-intention trmeor, wide stance, and difficulty with tandem stance and gait.

Extracerebellar signs and related diseases:3,4 Orthostatic hypotension, dysphonia, dystonia, pyramidal signs, and parkinsonism: MSA-C (the most common non-genetic degenerative ataxia).

Dystonia, Parkinsonism: Several SCAs; Wilson’s disease and Neuroacanthocytosis (NAC) in a younger cohort.

Action tremor, dysexecutive syndrome, neuropathy, Parkinsonism: Fragile-X tremor ataxia syndrome (FXTAS).

Chorea: Huntington disease, HD; DRPLA; SCA 17; Ataxia telangiectasia, AT; SCAs.1,2,3

Myoclonus and cognitive impairment: hepatic encephalopathy; CJD; anti-GAD syndrome; POLG (polymerase g) mutation.

Pyramidal signs, sensory loss: acquired myelopathies; genetic myelopathies [adrenomyeloneuropathy; hereditary spastic paraparesis (HSP)]; Friedrich’s ataxia (FA); MS; NS.

Sensory loss, hyporeflexia: AR ataxias; SPN and SG (“sensory ataxia”); GA; MF; AVED; NS.

Cognitive and psychiatric: CJD; Wernicke- Korsakoff syndrome; some genetic ataxias including SCA 17 and those associated with inborn errors of metabolism; leukodystrophies; NS; Whipple’s disease.

Eye-movement abnormalities: MS; ataxias with oculomotor apraxia 1 and 2 (AOA1, AOA2); SCA 2; Whipple’s disease; Ataxia telangiectasia, AT; MF.

Visual loss: MS; AVED; SCA7; mitochondrial disorders.

Telagiectasias: AT.

Achilles xanthomas and early cataracts: Cerebrotendinous xanthomatosis, CTX.

What diagnostic tests are recommended for ataxia evaluation?1,2

Brain MRI is indispensable. It may reveal:

Structural lesions and strokes.

Atrophy of the cerebellum and brainstem: chronic processes such as genetic ataxias.

Abnormal signal and atrophy of the basal ganglia: Wilson’s disease; HD; mitochondrial disorders; NAC.

Putaminal atrophy and cruciform hyperintensity in the pons (“hot-cross bun” sign): MSA-C.

Middle cerebellar peduncle lesions: FXTAS.

White matter abnormalities: MS; adult-onset leukodystrophies (Alexander disease; Adrenoleukodystrophy, ALD).

Diffusion-weighted abnormalities (“cortical ribboning”) and symmetric thalamic changes (“pulvinar” sign): CJD Spinal cord MRI is suggested for myelopathic signs.

Severe cord atrophy: FA; Alexander disease

Additionally, serum testing may be indicated and is guided by the clinical evaluation and imaging:

First tier: blood chemistries; renal and liver function tests; ammonia; complete blood counts with differential (CBC diff); erythrocyte sedimentation rates (ESR); Antinuclear antibodies (ANA); thyroid and vitamin levels (B12, B1, E); folate; glucose tolerance test; methylmalonic acid; infectious serologies (HIV antibody, Lyme antibody, RPR); Serum protein electrophoresis with immunofixatoin (SPEP with IFE).

Second tier (tests for rare ataxias and potentially treatable conditions, to be ordered if 1st tier testing is inconclusive): creatine kinase; lactate; pyruvate; α-fetoprotein (elevated in AT and AOA 2); fasting lipid profile; paraneoplastic antibodies (Hu, Yo, Ri, Ma, TA, CARP8, CV2, Tr, LEMS, MGLUR1, CRMP5, GQ1b, amphiphysin, PCA-2, NMDA, VGKC, ganglionic acetylcholine receptor antibodies); anti GAD65 antibodies; SSA, SSB antibodies (Sjögren’s antibodies); antigliadin antibodies (IgA and IgG); serum iron studies; alkaline phosphatase; thyroperoxidase (TPO) antibodies; 24 hour urine copper and zinc; serum copper and ceruloplasmin; urine heavy metals; Human T-Cell lymphotropic virus I, II; T. Whippelei PCR; cholestanol levels (if CTX is suspected)

Third tier (rarer genetic conditions typically seen in a younger cohort with ataxia and other symptoms such as dystonia, peripheral neuropathy, visceral involvement and cognitive impairment): peripheral blood smear for acanthocytes (for NAC); lysosomal screen; plasma amino acids; urine organic acids; serum ketones; fasting very long chain fatty acids (for ALD)

Cerebrospinal fluid studies are obtained for paraneoplastic, immune-mediated, infectious, and inflammatory disorders: protein; glucose; CBC diff; cultures; IgG synthesis, index, rate; oligoclonal bands; cytology; lactate; 14-3-3 protein; paraneoplastic antibodies; viral encephalitis panel; VDRL.

CT or PET scan of the body may be indicated to look for occult malignancy. Additional tests that may be helpful in certain settings include EEG, Electromyogram and nerve conduction studies, autonomic, or sleep study (to look for REMBD). Nerve and muscle biopsies are used for suspected mitochondrial ataxias or brain biopsy for suspected leukodystrophies. Other rarely indicated tests include magnetic resonance spectroscopy of the brain, dopamine transporter SPECT (DaT) scan (typically abnormal in MSA-C), or genetic tests.

The literature offers a detailed discussion of genetic ataxias. 6,7 The patient should be appropriately counseled about the implications and costs of genetic testing before it is ordered. Testing may reveal:

AD mutations: SCAs (most common worldwide is SCA 3 or Machado-Joseph disease), DRPLA, and the rare episodic ataxias (EA 1, EA 2).

AR mutations: have usual age of onset <20 years but later onset FA, AT, AOA 2 have been reported; POLG mutations.

X-linked mutation (premutation in the FMR1 gene): FXTAS.

Mitochondrial DNA mutations.

Specialized gene tests for inborn errors of metabolism, leukodystrophies, and storage disorders should be ordered if the evaluation raises suspicion for these rare conditions.

What if no cause is identified after extensive testing?

A large number of sporadic ataxias do not seem to have an identifiable etiology. When followed over time about onethird of ILOCAs may evolve to MSA-C1 Unidentified genetic mutations may account for the rest of these ataxias.

How are ataxias treated?

Specific interventions for acquired ataxias include steroids and other immunomodulating therapies for SREAT, paraneoplastic disorders, and immune-mediated ataxias. When an underlying malignancy is detected, it must be treated. Gluten-free diets are indicated for GA. Specific pharmacologic agents include acetazolamide is used for EA2, SCA 6 and varenicline (Chantix®) for SCA 3.7 Bile acid replacement may be tried for CTX.

Common sense measures include elimination of general medical conditions; correction of deficiency states; and, treatment of general medical disorders causing ataxia.

Non-specific pharmacological agents of potential benefit include amantadine, alpha-lipoic acid, buspirone, branchedchain amino acids, creatine, coenzyme Q10, vitamin E, physostigmine, riluzole, and selective serotonin reuptake inhibitors. Cerebellar tremor may improve with primidone and antiepileptics; oscillopsia with memantine and GABA agonists; and spasticity with central anti-spasticity drugs.

A multidisciplinary approach is necessary in MSA-C, due a multitude of progressive motor and non-motor symptoms. Rehabilitative therapies should be offered to all patients with ataxia. Continuous exercise programs have shown positive results.8

Summary

The diagnostic approach to adult onset ataxias should be systematic and guided by the history and examination. Non-genetic ataxias may involve an extensive and expensive evaluation that may be done in a tiered fashion. MSA-C is the most common sporadic ataxia. ILOCA is a diagnosis of exclusion.

A positive familial history signals a genetic disorder. Patients undergoing genetic tests should be appropriately counseled.

Effective management of ataxic disorders requires a multidisciplinary approach involving disease-specific and symptomatic drug treatment as well as rehabilitative measures.

8 Replies

Oh my. I need to research a lot to understand all these terms.

But I'm amazed that here I've had the electromyogram and nerve conduction tests, and the magnetic resonance spectroscopy tests. Which were done along with blood tests when ataxia was initially diagnosed.

I wonder how many others have had these tests? It would be interesting to know.

Despite all these tests my type of ataxia is still unknown

Thank you!

I really appreciated reading this article. I have been suffering with an ataxia style gait for the past 7 months. Nobody at my GP's had ever experienced this, so was wrongly sent to the wrong medical department (cardialogy) I have drunk walk and wobbliness symptoms on repeat. I have a small exercise window of around 6-8 minutes. The waiting list for a neurologist is around 48 weeks in my area.

My GP seems to have no urgency in my situation, hence 7 months down the line I'm still shouting and getting no where. Seen neurologist whilst on Cardiac ward in December, had EMG & NCS tests, but nothing since, as now in the "waiting drawer"

😏 I empathise, and I’d bet I’m not the only one...sometimes it can be a hit and miss affair as to whether a GP refers to the appropriate department, Neurological symptoms can ‘overlap’ other conditions muddying the waters. But the referral time to the Neurologist does seem awfully long.

🤔 Could you ask your GP to contact the Neurology Department, and mention you would take a cancelled appointment at short notice.

I'm already on that one. Sadly this is the same scenario with the Cardiac department, there were no appointments, so I sat waiting, shouting and screaming and all the time in the wrong department. Nobody accepted what I was saying, as if I'm not having an episode I look perfectly well 🙄 they continually said it was syncope and heart related. Whilst I argued it wasn't at all syncope, I never felt dizzy or collapsed, I walked unsteady or wobbled and tottered backwards or sideways until I had to sit down or I'd fall down.

Have contacted his secretary this morning, and now my continuous questioning for care begins again.

Dear Wobblybee, Thank you for posting all the interesting information! I was diagnosed with Sporadic Cerebellar Ataxia (idiopathic/unknown cause) at 49 years of age, although I had extremely minor symptoms starting at about 43 years of age. My neurologist had no idea 'why' I had ataxia, as all the domninent and recessive genetic tests I had over the years always came back negative. Finally, in 2017, I had genetic exome testing, as my neurologist suspected I had ARSACS (Autosomal Recessive Spastic Ataxia Charlevois-Saganay), which is a rare form of ataxia. Although the testing was negative for that, a single Niemann Pick C (NPC) gene was found. Therefore, after a skin biopsy followed by a blood test, it was determined I had ataxia due to NPC disease (which is recessive, which means, in my case, I got a NPC gene from one of my asymptomatic parents, and an unknown variant from the other parent). I not only have a single NPC gene, but an unknown variant as well (it takes double NPC genes to realize the disease). Late/adult onset NPC is extremely rare, which is what mine is. So after having ataxia 20+ years (I'm almost 66 years of age now) I finally found out why! My first neurologist (he retired) always told me "someday the cause will reveal itself" and he was right, as it did! There is no cure or FDA (Food and Drug Aministration) approved medications (I live in the USA) for NPC disease! It just gives me some peace of mind to finally know 'why' I have ataxia! I also have two grown children and wanted to know the possible implications for them and their children (my dear grandchildren). My best to you..., ;o)

I have been recently been diagnosed with Cerebellar Ataxia. I think that one of the main causes is my use of Xanax for about 10 years. My Neurologist told me then that the Xanax would help with my dizziness. It did for a while then got far worse, so since I was on a kinna low dose of a half mg a couple times a day...I just stopped. Had anxiety for a while but better than the dizziness. Stopped January 3, 2020. So then went to The Cleveland Clinic to find the cause. They found it easily an now not on any meds for it although the dizziness is horrible at times. Gets better later in the day to where I'm not falling. I was crushed to find that there is no cure and no medication that will really help. I'm 72 and live alone so it's hard to deal with on a never ending basis.

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