An 18 year old man joined the army as a soldier. Two weeks into the training the sergeant in charge of training the recruits reported him to the officer in the unit because the youngman would fall over while standing to “attention” and he could not learn to salute and had a tendency to be clumsy while handling a gun. He dressed clumsily and his shirt was usually buttoned wrong. He was sent to the doctor for an examination.
The doctor asked him to stand upright with his feet close together. The young man began to sway and had to hold on to a chair to steady himself. What is this? This is truncal ataxia. This is the equivalent to doing a Romberg’s test which is usually done for loss of sense of position or proprioception, vibration and touch.
The saluting process required him to stand upright with feet close together, stamp his right foot on the ground and raise his right hand upto his forehead with the palm held out and the left arm to be kept straight to his side. He would stamp his foot several times sometimes raising it too high and sometimes not enough. After stamping his foot he would try to raise his right arm which would reach his ear or top of his head or eye and the palm could not be held outward and the left arm would not remain still by his side. Not being able to do up his buttons correctly shows either apraxia or poor coordination.
The doctor asked him to walk along a straight line. He was clumsy and kept reeling from side to side. This shows gait ataxia. He did not have nystagmus nor did he complain of any visual disturbance except that when he was asked to point his gun at the target he said the target kept moving so that was why he could not aim the gun straight. What is happening here? He has visual ataxia and the muscles of the eyes cannot coordinate their movement.
What else should the doctor check in this patient? He should look for other signs of cerebellar dysfunction like nystagmus, loss of rapid alternating movements, slurring of speech, muscle tone (which will be lost in cerebellar ataxia, Friedreich ataxia and increased in atypical Friedreich ataxia), check the joints for ability to detect in which position the joint is being held, check for sense of vibration and touch. The tendon reflexes should be checked and would be expected to be lost, and the plantar reflex which in this case was upgoing.
What is the most probable diagnosis? On the basis of progressive limb and gait ataxia, dysarthria, loss of joint position and vibration senses, absent tendon reflexes in the legs,extensor plantar responses the doctor made a diagnosis of Friedreich ataxia.
What questions should the doctor ask? How long had he been “clumsy”? Did he tend to fall on the stairs? Did he have a problem hearing? Did he get breathless on walking long distances or on running? For cardiomyopathy. Are his parents first cousins? Are inter marriages common in his family?Are any other siblings or cousins suffering from similar symptoms? Has his blood sugar been tested in the past? Does he have problem controlling his urination?
This is an autosomal recessive ataxia resulting from a mutation of a gene locus on chromosome 9. FA was the earliest of the inherited ataxias to be distinguished from other locomotor ataxias and is the most common of the autosomal recessive ataxias.
Cardinal features are:
- progressive limb and gait ataxia.
- loss of joint position and vibration senses.
- absent tendon reflexes in the legs.
- extensor plantar responses.
- associated conditions are diabetes mellitus, cardiomyopathy, deafness, dysphagia, kyphoscoliosis and later in the disease loss of bladder control.
Atypical phenotypes. Approximately 25 percent of cases present with atypical symptoms and signs.
- Onset may be later than 25 years, cardiomyopathy usually does not occur and progression is slow
- Friedreich ataxia with retained tendon reflexes
- There may be leg spasticity with little or no gait and limb ataxia
- Rare cases of Friedreich ataxia can present as a Huntington disease phenocopy.
Neuro-imaging. An MRI will show atrophy of the posterior columns and medulla with little or no cerebellar atrophy.
Symptoms related to cardiac involvement include palpitations from arrhythmias and dyspnea and exercise intolerance caused by the cardiomyopathy, which is usually present but frequently asymptomatic until late in the disease course. To rule out cardiomyopathy do an ECG and echocardiogram. These will show changes characteristic of the usually hypertrophic cardiomyopathy of Friedreich ataxia. The main clinical manifestations are arrhythmia and heart failure, which are a frequent cause of death.
How can we confirm the diagnosis of Friedreich ataxia?
- Genetic testing for the triplet repeat expansions in the first intron of the frataxin (FXN) gene that cause Friedreich ataxia should be performed in all patients with progressive cerebellar ataxia and autosomal recessive inheritance.
- Frataxin levels from blood samples or buccal cells using immunoassay methods can identify individuals with Friedreich ataxia and presymptomatic carriers, and may be useful in rare cases where genetic testing has not identified a pathogenic mutation
- When the diagnosis is uncertain, serum alpha-tocopherol (vitamin E) levels should be checked; levels are typically normal in patients with Friedreich ataxia, while very low levels are suggestive of ataxia with vitamin E deficiency.
- Neuro-imaging as detailed above.
- ECG and echocardiogram for cardiomyopathy.
- Blood sugar testing for diabetes usually requiring insulin.
- Evidence of a sensory axonal neuropathy on electrodiagnostic testing is a supportive feature for the diagnosis while the absence of neuropathy does not exclude the diagnosis.
- Check serum cholesterol, triglycerides and beta lipoprotein levels.
Differential diagnosis includes:
- Ataxia-telangiectasia (AT), an autosomal recessive genetic disorder.
- The Roussy-Levy variant of Charcot-Marie-Tooth disease, which is an autosomal dominant disorder that can present with areflexia and ataxia.
- Ataxia with vitamin E deficiency, an autosomal recessive disease caused by mutations in the alpha tocopherol transfer protein gene.
- Abetalipoproteinemia (Bassen-Kornzweig disease), an autosomal recessive disorder caused by mutations in the microsomal triglyceride transfer protein gene, which leads to impaired fat absorption, abnormally low serum concentrations of total cholesterol and triglyceride, and absent serum beta lipoprotein. The neurologic manifestations include progressive retinal degeneration, peripheral neuropathy, and ataxia. Vitamin E administration may help.
- Refsum disease, a rare autosomal recessive peroxisomal disorder characterized by retinitis pigmentosa, ichthyosis, sensorimotor polyneuropathy, and cerebellar ataxia. Strict reduction in phytanic acid in the diet is likely to help.
There is no disease modifying therapy for Friedreich ataxia. Gene therapy is still in research, antioxidant therapy such as idebenone, vitamin E and iron chelation therapy may help.
I am passing on these guidelines taken from Medscape to which many of you may not have access. You can see these guidelines for yourself.
Diagnosis and Treatment of Progressive Ataxias Clinical Practice Guidelines (2019) – Medscape – Mar 26, 2019.
Ataxia in adults can be caused by serious neurological disease. Offer urgent referral for secondary care (ie, neurologist) following the primary care investigation.
Urgent pediatric assessment is recommended for children presenting with ataxic symptoms. The pediatric assessment is usually performed by a local specialist, who may then cooperate with pediatric neurologists and clinical geneticists, among others.
Rapid progression (eg, over weeks or months) may herald a prion disease, multisystem atrophy, or paraneoplastic cause; urgent investigation is required.
To determine the type of treatment for spasticity, a careful assessment by a neurologist in cooperation with advice from a physiotherapist is required.
Physiotherapy should be considered first to treat spasticity. If physiotherapy does not provide complete results, pharmacological treatment should be used. Consider surgery if neither physiotherapy nor pharmacological treatments are successful.
The following oral medications should be considered for generalized spasticity, usually in the order given, owing to adverse effect profile and tolerability: baclofen, tizanidine, gabapentin, clonazepam, dantrolene sodium, or diazepam.
For focal spasticity, refer the patient to a specialized clinic for intramuscular botulinum toxin injections, with physiotherapy to follow.
Tremor. The following medications (in order) should be offered as pharmacological treatment for patients who have ataxia and tremors: propranolol, primidone, propranolol/primidone combination treatment, topiramate, clonazepam, or gabapentin. For extremely debilitating tremors nonresponsive to pharmacological treatment, consider referring patients to a center that specializes in functional neurosurgery.
Dystonia. Treat focal dystonia with botulinum toxin injections. Treat generalized dystonia with oral medications, with surgical treatment to follow if pharmacological treatment is not effective.
Offer physiotherapy and oral medications to patients with dystonic tremor, to be followed by surgery if physiotherapy and oral medications are not effective.
It is recommended to conduct regular surveillance for the development of scoliosis in patients with Friedreich ataxia. If it is detected, it is recommended that the patient be referred to a physiotherapist and spinal surgeon.
Patients with mild scoliosis should be closely observed; the spinal surgeon should consider treatment with bracing.
Patients with severe scoliosis should be considered for surgery to straighten the spine.
Drugs to consider for treatment of neuropathic pain include amitriptyline, nortriptyline, carbamazepine, pregabalin, gabapentin, and duloxetine.
If pain is severe or is limiting daily activities, consider referral to a pain management clinic.
Cardiac involvement in Friedreich ataxia
Patients diagnosed with Friedreich ataxia should be referred to a cardiologist for early surveillance for cardiac problems and complications.
These patients should receive regular screening by a cardiologist at intervals of once every 2 years before any cardiac disease is documented and then at least annually if features of asymptomatic cardiac disease manifest.
Use transthoracic echocardiography and electrocardiography for diagnosing and monitoring myocardial changes.
Use Holter monitoring to detect silent cardiac arrhythmias or symptoms (eg, palpitations, dyspnea) associated with the underlying rhythm.
Bladder problems (lower urinary tract dysfunction)
To exclude common causes of urgency and frequency, test for urinary tract infection and measure post void residual. If results are within normal limits, investigate other common causes (eg, prostate enlargement).
Offer practical advice such as reducing intake of caffeine, carbonated beverages, and alcohol. Additionally, offer information about timed voiding and bladder retraining if appropriate. Fluid intake should be individualized; 1-2 L/day is recommended, depending on possible concurrent cardiac issues.
Offer advice on pelvic floor exercises; these may be helpful if symptoms are mild.
In most individuals with overactive bladder, antimuscarinic medications such as tolterodine, oxybutynin, propiverine, or solifenacin are required. Caution is advised when using antimuscarinic medications in patients with cardiac complications and/or cognitive problems. Consider using more selectively acting antimuscarinic agents (eg, trospium chloride, darifenacin) in patients with cognitive problems.
For patients with constipation, offer suggestions for lifestyle changes, such as diet, fluids, and mobility assistance. Follow up with laxatives or suppositories as necessary.
If patients have urgency or fecal incontinence, consider referring them to a specialist for assessment.
Owing to the potential for erectile dysfunction, consider discussing sexual function with male patients.
If appropriate, erectile dysfunction can be treated with phosphodiesterase-5 inhibitors. Base treatment decisions on patient needs and the potential adverse effects of the medications (eg, hypotension).
Exercise caution with medication selection in patients with cardiac pathology; cardiologist consultation is recommended.
Swallowing, dysphagia, and sialorrhea (excessive salivation)
Referral to a speech and language therapist should be made if patients show symptoms of dysphagia.
If dysphagia is resulting in unintentional weight loss, consider nutritional supplementation and referral to a dietician.
Percutaneous gastronomy may be needed to provide reliable feeding if caloric intake cannot be maintained despite supplements.
Sialorrhea is usually associated with dysphagia; speech and language therapist referral is recommended, as is treatment for the sialorrhea and thick secretions.
Audiology and hearing issues
Refer patients experiencing hearing problems to an audiologist for full hearing tests.
If a patient has ataxia with auditory neuropathy spectrum disorder, a trial with a frequency modulation hearing device is recommended.
If patients develop disabling nystagmus or oscillopsia, treatment is recommended (eg, with either gabapentin or baclofen).
In patients with diplopia, referral to an optometrist or neuro-ophthalmologist is recommended for restoration of single vision with prisms.
Visual impairment in ataxia patients warrants correction with low-vision aids and possible official registration of visual disability.
Inherited episodic ataxias
Patients with episodic ataxia should be advised on identifying potential attack triggers and avoiding them. Such triggers may include stress, caffeine and alcohol consumption, and excessive physical exertion.
For episodic ataxia types 1 and 2, the first-line recommended drug is acetazolamide (not all patients respond).
Patients taking acetazolamide should be advised to stay well-hydrated to prevent renal calculi formation; periodic screening of the urinary tract with ultrasonography is warranted.
If the patient has a known hypersensitivity to sulfonamides, keep him or her under surveillance during treatment.
If acetazolamide is not beneficial for episodic ataxia type 2, consider using 4-aminopyridine on a named-patient basis as a second-line option.
Carbamazepine, phenytoin, or lamotrigine can be considered as second-line options in episodic ataxia type 1.