Introductory Chapter: Insights into Ataxia

1. Introduction

The term “ataxia” or also “distaxia” means the inability to coordinate, but at the same time, it is also used to describe the group of underlying neurological disorders that affect coordination, balance, and speech. The delineation of ataxic disorders as distinct entities can be said to have begun with the description of siblings with ataxia by Nicholas Friedreich in the 1860s, suggesting a genetic etiology, though there are possible descriptions of similar disorders antedating this [1, 2, 3].

Ataxic disorders also refer to symptoms that affect the coordination of these movements. They may be a symptom of several degenerative medical or neurological conditions of the nervous system that compromise the movements of different regions of the body — fingers, hands, arms, legs, eyes, balance, muscle tone, swallowing, and speech. It can also be manifested as a lack of coordination that impairs voluntary movement as a whole. The common symptoms of ataxia are similar to those of a drunk such as slurred speech, stumbling, falling, and incoordination [4, 5].

The number of ataxia subtypes is unknown, but it is estimated that there are at least 100 different subtypes, each with a distinct etiology. To date, current classifications subdivide ataxias into three large groups: (i) degenerative ataxias, (ii) hereditary ataxias, and (iii) acquired ataxias related to exogenous or endogenous non-genetic insults [5].

The purpose of this chapter is to provide a brief introduction for academics and clinicians with introductory tips for understanding, evaluating, and managing ataxias in general.

2. Pathophysiology of ataxia

Ataxic disease is most commonly caused by dysfunction of the cerebellum or its pathways, including impairment of vestibular or proprioceptive input to the cerebellum [6, 7]. Cerebro-cerebellar connectivity is organized into multiple circuits that function to connect devices in parallel. Depending on the location of the cerebro-cerebellar connectivity injury, the characteristic findings regarding ataxic disorders are generally the following: Lesions affecting the lateral portion of the cerebellum lead to ipsilateral symptoms, while lesions affecting diffusely can lead to generalized symptoms. Lesions affecting the cerebellar hemisphere lead to appendicular ataxia. While insults within the vermis lead to postural gait ataxia with limb preservation. Lesions in the vestibulocerebellar areas cause gait imbalance, vertigo, and ataxia [8, 9, 10].

Taking into account the clinical scenario, according to Cabaraux et al., 2021, cerebellar symptoms of cerebellar injury can be grouped into three main cerebellar syndromes:

1. Cerebellar Motor Syndrome, when lesions generally affect the lobes I-V, VI, and VIII and where patients present different combinations of speech alterations (scanned, explosive, and nasal voice), mutism, limb ataxia with loss of coordination (dysmetria, dysdiadochokinesia, tremor, hypotonia, cerebellar convulsions, and other related conditions), defective writing, gait staggering, and steadiness and impaired motor skills.

2. Vestibulocerebellar Syndrome when injuries occur in the vestibular nuclei that are connected to lobes IX–X and the dorsal oculomotor vermis corresponding to lobes V–VII are affected in these cases and is characterized by various combinations of dysmetria, saccadic pursuit, nystagmus, impaired vestibulo-ocular vision, oblique gaze deviation [8, 11, 12].

3. Schmahmann Syndrome or Cerebellar Cognitive-Affective Syndrome when lesions affect lobes VI-IX and patients present different combinations of dysexecutive, visuospatial, linguistic deficits and affective dysregulation that is characterized by changes in executive functions (management, factual situation, abstraction, verbal fluency, memory) and may also present a lack of attention; disorganization and affected visuospatial memory; personality change with affective changes and inappropriate behavior; and language difficulties [13, 14, 15].

The ataxic diseases can generally be the result of a considerable variability of causes, and there can be numerous etiologies for ataxias, which can occur isolated or simultaneously, acutely or chronically, and at any age, both in children and in adults and even common in the elderly [6, 7, 8, 9, 10].

Findings from the physical examination, in combination with the assessment of risk factors and presentation of the complaint, lead to a decision. Ataxia also can be seen in 30–60% of patients with posterior circulation stroke [14, 15]. Patients may present atypically and with multiple causes that may exist simultaneously. This contributes to the important clinical heterogeneity of ataxic disorders in daily practice [8].

However, studies have shown that misdiagnoses of posterior circulation strokes are frequent, with dizziness and difficulty walking more likely to be manifested than focal weakness, changes in vision, or neglect [10, 11, 12, 13, 14, 15]. In emergency care, attention should be focused on treatable and reversible etiologies of ataxia.

Hereditary ataxias represent a wide clinical spectrum of disorders, and phenotypic variability is recurrent between individuals suffering from the same ataxia subtype. It may be characterized by episodic, spinocerebellar, Friedreich’s, X-linked, and mitochondrial ataxia as well as sporadic conditions. Clinically, it is presented by progressive ataxia combined with extra-cerebellar and multisystemic involvements, including peripheral neuropathy, pyramidal signs, movement disorders, seizures, and cognitive dysfunction. Friedreich’s ataxia is the most common cause of an autosomal recessive pattern of inheritance, appearing between the first and second decades of life. The abnormalities affecting multisystem are seen and include myocardiopathy, endocrinological diseases, vision, and hearing loss. Gait ataxia, loss of sensory and proprioception, pes cavus, spastic extensor plantar responses, and extremities atrophies [6, 16, 17].

3. Common signs and symptoms and clinical assessment

On the physical examination of neurological ataxic patients, one of the main neurological symptoms and signs to be investigated when locating lesions in the nervous system with a complete neurological examination. Recognizing its importance becomes crucial, especially when it comes to changes in gait, changes in speech, and abnormal eye movements. Another ability to research related to ataxia refers to the inability to coordinate the position of the head, trunk, and limbs. Ataxia can also be a sensory dysfunction, and not just a motor one, which can only be identified when the patient moves. Remember that it can also be confused with motor impairment [18]. However, the main difference between ataxia and paresis is that ataxia affects coordination without affecting strength, while paresis affects only strength, and they are often confused with each other. However, the type of ataxia is characterized by a complete neurological examination (mental status, gait – postural reactions (mainly), assessment of cranial nerves, spinal reflexes, and pain perception), and the main causes of ataxia can be separated into vestibular, sensory ataxia, cerebellar, and antalgic [19].

Common signs and symptoms of ataxic patients include gait abnormalities, slurred speech, difficulty walking, abnormal eye movements, difficulty swallowing, increased fatigue, incoordination in fine motor movements such as handwriting, buttoning shirts, typing, tremors, vertigo, and cognition problems [20]. Clinicians should ask patients whether any of the signs and symptoms are present, the level of functional disability in activities of daily living, onset, and progression. At this point, the clinical assessment of ataxia can be performed by a set of ataxia rating scales [21].

There are several ataxia rating scales based on different ataxic populations, and four scales are highlighted following:

1. Scale for Assessment and Rating of Ataxia – SARA [22]

2. International Cooperative Ataxia Rating Scales – ICARS [23]

3. Friedreich’s Ataxia Rating Scale – FARS [24]

4. Unified Multiple System Atrophy Rating Scale – UMSARS [25]

Ataxia evaluative scales have psychometric properties such as feasibility, acceptability, consistency, and reproducibility. They are usually used in different ataxic populations [21] in a way that determines similarities and differences in the aspects of ataxia addressed. For example, SARA mainly assesses ataxia and motor performance, while ICARS is concerned with assessing vision and ocular motricity disorders. Autonomic functions and bulbar dysfunctions are assessed in both UMSARS and FARS. The SARA scale proves to be an ideal scale for rapid assessment of ataxia or in clinical settings that require rapid screening. UMSARS or FARS are more appropriate for assessing the impact of ataxia on general health, monitoring the progression of ataxia, activity of daily living, and the individual’s disability [26].

4. Essential evaluation and differential diagnosis

The progression of ataxia from symptom onset to maximum deficit is to be known whether it is acquired, genetic or non-hereditary sporadic degenerative. Acquired ataxias usually present acutely and progress rapidly from vascular, immune-mediated, infectious, and toxic causes. Substrate deficiencies (e.g., vitamin B1, B12, E, or A) and iatrogenic insults, other than acute drug overdose, present subacutely (Table 1) [27, 28].

Subtype	Etiology or related agent
Congenital	Developmental
Mass lesion	Tumor, Cyst, Aneurysm, Hematoma, Abscess, Normal Pressure, or Partial Obstructive Hydrocephalus
Vascular	Stroke, Hemorrhage, Subcortical Vascular Disease
Infections	Anthrax, Epstein–Barr, enterovirus, HIV, HTLV, Prion disease, Lyme Disease, Syphilis, Measles, Rubella, Varicella, Whipple’s Disease, and Progressive Multifocal Leukoencephalopathy
External causes	Post-Anoxic, Post-Hyperthermic, Post-Traumatic
Epilepsy	Long-Standing Epilepsy
Systemic	Acute Thiamine (B1) Deficiency, Chronic Vitamin B12 and E Deficiencies, Autoimmune Thyroiditis, and Low Thyroids Levels
Toxic	Common Drug Reaction (Amiodarone, Cytosine Arabinoside, 5-Fluorouracil, Lithium, Phenytoin, Valproic acid} Environmental (Acrylamide, Alcohol, Organic Solvents, Organo-lead/Mercury/Tin, and Inorganic Bismuth/Mercury/Thallium)
Immunological	Vasculitis (Giant Cell Arteritis, Behcet’s disease, Systemic Lupus Erythematosus, and others). Paraneoplastic (Anti-Yo, Hu, Ri, Ma Ta, CV2, Zic4, Anti-calcium channel, Anti-CRMP-5, ANNA-1,2,3; mGluR1, and TR). Autoimmune disorders (Anti-GluR2,GAD, MPP1, GD1b ganglioside, and anti-gliadin)

Table 1.

Identifiable causes for non-hereditary ataxia.

Adapted from Evaluation and Management of Ataxic Disorders [27, p. 2].

A detailed history should be obtained to assist in identifying the cause of the ataxia. A detailed history and physical and neurological examinations should be performed. Neurological examination allows the clinician to identify the type of ataxia. Once the type of ataxia has been identified, other diagnostic tests should be performed according to the type of ataxia and the location of the lesion. Although most patients with ataxia have a primary neurological disease, it is important to know the cause can be metabolic disorders (e.g., hypoglycemia and hypocalcemia), toxins (e.g., lead and organophosphates), and medications (e.g., phenobarbital and metronidazole). Once a detailed history is obtained, physical and neurological examinations should be performed. The neurological examination can help clinicians to identify the type of ataxia. Once the type of ataxia is presumed, further diagnostic tests can be performed according to the type of ataxia and the lesion localization suspected [27].

Congenital diseases are also important causes of ataxia, specifically chronic ataxic syndromes such as Dandy–Walker Syndrome and Arnold Chiari Malformations. The Dandy–Walker syndrome is characterized by enlargement of the fourth ventricle in the posterior fossa, absence of the cerebellar vermis, and a cystic formation close to the internal base of the skull [28]. In Arnold Chiari malformations, the affected patient shows a downward displacement of the cerebellar tonsils through the foramen magnum with a presumed risk of complicating with a non-obstructive hydrocephalus [29].

Genetic ataxias can be highlighted as an autosomal dominant, autosomal recessive, or X-linked manner inheritance. The presence of a genetic disease does not exclude the presence of an acquired etiology that may alter the presentation and course of ataxia symptoms and warrant further investigation. Likewise, the absence of a clear family history does not exclude the role of genetics within an apparently sporadic disorder. Often, the fact that family history has not been adequately obtained because the information is not straight available (adoption, loss of contact, non-cooperation, and paternity issues), due to non-dominant inheritance patterns (recessive, X-linked, and maternal/mitochondrial) or due to specific genetic processes that modify the presentation of the disease in the pedigree (anticipation, incomplete penetrance, and mosaicism) [24].

Adult-onset genetic ataxias may not appear to clinicians until later in the course of the disease due to their insidious onset and slow progression.

Progressive muscular atrophy appears much more quickly compared to tardive idiopathic ataxia and genetic ataxia, causing significant disability in a short space of time, with death occurring 6–10 years after the onset of symptoms. Genetic counseling and risk assessment depend on determining the specific cause of hereditary ataxia in an individual.

5. Variability in rate or progression

The ataxia disorders may be associated with very specific causes. When the onset of symptoms occurs acutely and abruptly, it may be related to vascular and/or structural brain damage. While rapid onset over hours-days is more associated with infectious or parainfectious cerebellitis, immune-mediated diseases such as Miller–Fisher syndrome, acute exposure to toxins, metabolic insult, or multiple sclerosis [27, 28]. Onset that occurs over weeks to months is associated with paraneoplastic disorders: anti-glutamic acid decarboxylase antibody syndrome, steroid-responsive encephalopathy and ataxia, gluten ataxia in celiac disease, vitamin deficiency states, general medical conditions such as hepatic encephalopathy, infections, sensory polyneuropathy, and ganglionopathy.

The long-standing progression occurring over the years is associated with genetic ataxias and may vary according to the individual: toxins, multiple sclerosis, storage disorders, sporadic neurodegenerative disorders, atypical parkinsonian conditions such as progressive supranuclear palsy or neurosyphilis. All possible etiologies must be considered when the clinical course is not fully determined. They must be differentiated from disorders such as dystonia, parkinsonism, chorea, myoclonus, cognitive impairment, pyramidal signs, sensory loss, hyporeflexia, cognitive and psychiatric symptoms, eye movement abnormalities, visual loss, neuromuscular deficits, telangiectasias, Achilles xanthomas, and early cataracts [30].

6. Further diagnostic tests

The following diagnostic tests as magnetic resonance imaging of the brain and spine, in addition to serum tests that can be indicated and guided by clinical and imaging evaluation, studies of the cerebrospinal fluid are obtained for paraneoplastic, immune-mediated, infectious and inflammatory disorders: protein, glucose, different blood count, cultures, IgG synthesis, index, rate; oligoclonal bands, cytology, lactate, 14-3-3 protein, paraneoplastic antibodies; viral encephalitis panel and Venereal Disease Research Laboratory test levels.

In case of suspicion of occult malignancy, a CT scan or PET scan of the body may be indicated. Further diagnostic testing that may be helpful in certain situations includes electroencephalogram, electromyography, nerve conduction studies, autonomic studies, or sleep studies. In selected cases, nerve, muscle, and brain biopsies are used for suspected mitochondrial ataxias in leukodystrophies or idiopathic etiology. Other rarely indicated tests include magnetic resonance spectroscopy imaging of the brain and dopamine transporter single photon emission computed tomography (SPECT) (DaT) scan (abnormal in MSA-C and other specific illnesses). Specialized genetic testing for inborn errors of metabolism, leukodystrophies, and storage disorders should be ordered if the remainder of the evaluation raises suspicions about these rare conditions. The patient should be adequately counseled about the implications and costs of genetic testing before ordering [6, 27]. Several sporadic ataxias do not have an identified cause. When followed over time, about one-third of Idiopathic Late Onset Cerebellar Ataxia can progress to MSA-C. Unidentified genetic mutations may be responsible for the remainder of ataxias (Table 2) [28, 31].

MRI brain and spinal cord, with and without contrast, with diffusion-weighted imaging (DWI) sequences Additional imaging:. MR spectroscopy or positron emission tomography (PET) scan/dopa-PET scan Electroencephalogram and Evoked Potentials (Visual, Auditory, Somatosensory) Electromyogram with nerve conduction studies Chest X-ray First-line lab checks: CBC, chemistry panel, HgbA1c, fasting lipids, ERS, ANA, RPR, TSH; vitamin E, folic acid, and vitamin B12 levels; methylmalonic acid, homocysteine, and urine heavy metals Second-line lab checks: CPK, SPEP, postprandial lactate-pyruvate-ammonia, ketones, copper, ceruloplasmin, zinc, ACE, Lyme diseases titers, HTLV I/II, HIV, anti-thyroid antibodies, anti-gliadin antibodies (and anti-endomysial/anti transglutaminase antibodies), anti-GAD antibodies (and anti amphiphysin antibodies) Third line lab checks: very long chain fatty acids/phytanic acid, urine and plasmatic amino acids, urine organic acids, lysosomal hydrolase screen including hexosaminidase A, coenzyme Q10 levels, glutathione levels, PRPN gene analysis Spinal fluid studies: cell count, glucose, lactate, protein, VDRL, gram stain, cultures as appropriate, cryptococcal antigen, 14-3-3 protein, neuron-specific enolase, prion protein studies, neurotransmitter levels as appropriate, myelin basic protein, oligoclonal bands, IgG synthesis Biopsies: conjunctival, muscle/nerve, GI tract, bone marrow, brain Paraneoplastic workup: tailored imaging(ultrasound, CT, and MRI), alpha fetoprotein, paraneoplastic antibodies (Yo, Hu, Ri, CV2, MaTa, Zic4, and others) Genetic workup if no family history of ataxia: Gene tests for SCA6, SCA3, SCA1, Friedreich ataxia, and fragile X-associated tremor/ataxia syndrome. Inborn errors of metabolism. Clinical whole exome sequencing

Table 2.

Workup for patients with ataxic disorders.

Adapted from Evaluation and Management of Ataxic Disorders [27, p. 4].

7. Treatment and management

Specific interventions include steroids for paraneoplastic and other immunological disorders as well as immunomodulatory therapies for steroid-responsive encephalopathy associated with Hashimoto’s encephalopathy. General measures include eliminating toxins, compensating metabolic states, and treating deficiency disorders [29].

Pharmacological agents of the nonspecific type include amantadine, alpha lipoic acid, buspirone, branched-chain amino acids, creatine, coenzyme Q10, vitamin E, physostigmine, riluzole, and selective serotonin reuptake inhibitors. Specific agents include acetazolamide used for AS2, ACS type 6, and varenicline for spinocerebellar ataxia. Bile acid replacement may be attempted for cerebrotendinous xanthomatosis. Diets such as gluten-free are indicated for gluten ataxia.

Cerebellar tremor may improve with the use of antiepileptic drugs, oscillopsia with memantine and GABA agonists, and spasticity with antispasticity-type medications [30].

A multidisciplinary approach to ataxic disorders may be necessary due to the variability and progressiveness of motor symptoms and non-motor symptoms. Rehabilitation therapies should be offered to all patients with ataxia. Continuous exercise programs have been shown to be effective with positive results [32].

The proposed outline summarizes all potential symptoms clinicians may need to address when facing an ataxic patient. Treatment strategies are often derived from other neurological conditions with similar symptoms and often work. For example, the approach to treating spasticity and bladder symptoms is the same as for people with multiple sclerosis. Assessment and management of these complications are best accomplished with the involvement of therapy specialists, and multidisciplinary teamwork can greatly improve patient care. Carrying out speech therapy is fundamental in the patient’s management, including monitoring the swallowing function in the initial stages and seeking to avoid complications while trying to plan nutrition through alternatives such as percutaneous gastrostomy and others (Figure 1) [30, 32, 33, 34].

Figure 1.

Common Symptoms of Ataxic Patients and its Treatment Strategies. Extracted from Ref. [9].

8. Final remarks

Due to the very particular nature of ataxia, it is necessary that diagnoses, symptoms or “severity” be evaluated in research targeted at the affected population. It is relevant because, although an intervention may be useful for a population with ataxia who share the same characteristics (e.g., speech problems), it may not be useful without modification for other individuals with other characteristics (e.g., problems that are not problems speech).

To better address the efficacy and safety of treatments for degenerative or hereditary ataxia, longitudinal studies in this field of investigation are also needed. The multidisciplinary team is unquestionably important in the diagnosis and treatment of patients with ataxia. Patients with ataxia typically receive evaluations several times a year, ideally by a specialized team that includes a neurologist, an advanced palliative care nurse, and, as needed, additional medical professionals such as psychiatrists, physiatrists, social workers, palliative, and others.

An important point to remember is that its diagnosis can be more difficult due to the overlapping of phenotypes of different etiologies. Once the common and uncommon presentations of ataxia have been detected, the diagnostic process can be aided by medical history and clinical features, as with any neurological condition. The essential interventions of ataxia disorders can be unraveled through knowledge of the pathophysiological aspects to gain an overview of ataxia along with reading contemporary and up-to-date evidence-based information in various settings. A key point is the correlation of the scenario and age group, identifying whether the disorder appeared in early childhood or even in adulthood and old age. It is the role of an interprofessional team to evaluate the care and management of patients with ataxia, and it is also fundamental, in this case, to take into account the opinions and listen carefully to the patients themselves, caregivers, and professionals involved in forming guidelines for interventions based on their own experiences. The World Health Organization (WHO) highlights September 25 of each year as the international day to raise awareness of these symptoms related to ataxia and this little-known neurological disease, which can sometimes have genetic and hereditary origins.

Finally, future research is imperative to determine whether patients with ataxia can benefit from any type or amount of intervention, according to this review of the intervention domain, as well as improving the ability to detect and differentiate diseases, especially considering that it is a disease, syndrome, and symptom at the same time.