Treatable Ataxias.

Diseases of the cerebellum are now better understood and some ataxias may respond to treatment. Just a quick recapitulation of what the cerebellum consists of: there are the two hemispherical lobes which contain the dentate nuclei and the midline connecting structure which  includes the cerebellar vermis, the fastigial and interposed (globus and emboliform) nuclei, the vestibulocerebellum (composed of the flocculus and nodulus), and the paravermis/intermediate zone.

The patient has gait ataxia and imbalance, truncal ataxia, dysmetria, ocular findings, head bobbing, and vertigo. Where is the damage likely to be? The midline cerebellar structures which are critical for motor execution, rapid and slow eye movements, balance/lower extremity coordination, and vestibular function.

How does truncal ataxia present? The patient is unable to sit unsupported and must spread out his arms on the bench to stop from falling or prefers to sit in an armchair.

What abnormality will you see in the eyes in cerebellar damage?

The most common ocular abnormality is saccadic intrusions, which are irregular bursts of rapid eye movements that include opsoclonus, ocular flutter, square wave jerks, and macrosaccadic oscillations. These most often but not always result from cerebellar lesions. Another common ocular abnormality is horizontal gaze-evoked nystagmus. Often the nystagmus is more prominent when looking towards the side of the lesion, although nystagmus in all directions of gaze is usually present. Vertigo and nausea are usually associated with eye movements.

What will happen if the cerebellar hemispheres are damaged? The clinical signs most commonly seen include dysdiadochokinesis, dysmetria, limb ataxia, intention tremor, and scanning speech. So by examining the patient and seeing which abnormality is present you can guess where the damage is likely to be in the cerebellum.  If the patient has motor weakness and sensory loss and loss of proprioception, impaired vision  may mimic ataxia. Rule out hydrocephalus and vestibular disease.

Cerebellar ataxias can be divided into acute (seconds to days), subacute (days to weeks), and chronic (months to years) ataxias. For chronic and episodic ataxias, a second division into familial or apparently sporadic is also helpful. If there is edema of the cerebellum as in an infarct or a hemorrhage in the structure the patient presents as an acute neurological emergency. More often the disease is chronic degeneration and symptoms appear over months and years.

Acute ataxias are usually accompanied by headaches and are caused by:

  • Cerebellar ischemia. This can be caused by multiple mechanisms affecting the vertebrobasilar arterial system, including embolism, thrombosis, dissection, and vasculitis. In most cases, occlusion of the vertebral arteries, basilar artery, or the major branches feeding the cerebellar hemispheres results in ipsilateral limb ataxia and, in cases of damage to midline cerebellar structures, nystagmus, imbalance, vertigo, nausea, and vomiting. In addition, there can be associated brainstem findings that vary depending on the site of the lesion.
  • Intermittent cerebellar ataxia can be seen with vertebrobasilar insufficiency. Symptoms may worsen with posture of the neck.
  • Cerebellar hemorrhage may result from a number of etiologies, including hemorrhagic conversion of ischemic infarction, hypertensive hemorrhage, aneurysmal rupture, and bleeding from arteriovenous malformation.

Cerebellar swelling can lead to compression of the adjacent brainstem and the fourth ventricle, resulting in hydrocephalus from compression of cerebrospinal fluid outflow through the fourth ventricular foramina and eventually downward herniation and death if left untreated.

Don’t forget drugs.

  • Antiepileptic drugs, especially those that effect sodium channel conductance such as phenytoin, are associated with ataxia. In the same category are carbamazepine, oxcarbazepine, lacosamide, lamotrigine, rufinamide, and zonisamide. Ataxia is also seen with benzodiazepines, felbamate, phenobarbital, and valproic acid in the setting of hyperammonemia.
  • Chemotherapy can be associated with both reversible and permanent cerebellar ataxia. Cytarabine, often used in treatment of leukemias and lymphomas, and fluorouracil, which is used in various cancer treatments including colon cancer therapy, are the most common chemotherapeutics associated with acute cerebellar ataxia. High doses of cytarabine cause an acute cerebellar syndrome in 10 to 25 percent of patients 
  • Meningoencephalitis can produce symptoms of cerebellar ataxia with or without encephalopathy. Affected patients often have headache, neck stiffness, and fever, depending on the inciting agent. Varicella-zoster, Epstein Barr virus, meningococci, mycobacteria can all be responsible.
  • Postinfectious cerebellitis is a condition classically seen between one and six weeks after varicella or measles infections in children, but can also occur after Epstein-Barr or other viral infections and vaccinations in teenagers and young adults.

Subacute cerebellar ataxias can be seen in autoimmune diseases.

These may include acute disseminated encephalomyelitis, celiac disease (gluten enteropathy with ataxia), GAD antibody-associated ataxia, Hashimoto thyroiditis/encephalopathy, Histiocytosis X, the Miller Fisher variant of Guillain-Barré syndrome, multiple sclerosis (note overlap with postinfectious cerebellitis as initial presenting symptom), neurosarcoidosis, postinfectious cerebellitis (eg, following varicella zoster virus or Epstein-Barr virus infections), and vasculitis (including Behçet disease, polyarteritis nodosa, and temporal arteritis).

Look out for primary or metastatic neoplasms causing cerebellar symptoms as well paraneoplastic syndromes as seen in most frequent in lung cancer (particularly small cell lung cancer), gynecologic cancer, breast cancer, and lymphoma (mainly Hodgkin disease).

Alcohol associated cerebellar damage is seen in the direct toxic effects of alcohol, chronic malnutrition often seen in alcoholics and associated deficiencies in thiamine, vitamin B12, and vitamin E.

Wernicke encephalopathy results from a deficiency in thiamine and is characterized clinically by the triad of ataxia, delirium, and ophthalmoplegia. It is most often associated with alcoholism but is also seen in  severe malnutrition from any cause (particularly at the time of refeeding) and in dialysis patients. Treat with parenteral thiamine deficiency can cause a polyneuropathy and cerebellar ataxia.

Vitamin E deficiency. The disorder is uncommon but can occur with fat malabsorption and steatorrhea associated with primary biliary cholangitis, cholestatic liver disease, cystic fibrosis, small bowel bacterial overgrowth, pancreatic insufficiency, celiac disease, Crohn disease, and following gastric bypass.

Systemic disorders in which cerebellar insufficiency can be seen are listed below.

  • Acquired hepatocerebral degeneration is a progressive neurologic disorder that occurs in the context of repeated episodes of liver failure or chronic liver cirrhosis, with portosystemic shunting a probable risk factor.
  • Hypothyroidism, especially when severe and untreated, can be associated with ataxia.
  • Hypoparathyroidism, either primary or secondary, can be associated with multiple neurologic symptoms including ataxia, weakness, spasticity that can progress to tetany, numbness, neuropsychiatric symptoms, and seizures. Treat the hypocalcemia.

Treatable Ataxias
Gluten ataxia: Patients with idiopathic cerebellar ataxia should be tested for gluten sensitivity. If possible, consider testing for antibodies against TG6, which can be a more sensitive test for gluten ataxia. In ataxia patients with or without enteropathy who have serological evidence of gluten sensitivity, a gluten-free diet should be started immediately. These patients should be given dietetic advice and should be advised about strict adherence to the diet. Close monitoring is recommended; testing should be performed at 6-month intervals to ensure antigliadin antibodies are eliminated.

Ataxia with vitamin E deficiency: In ataxia with vitamin E deficiency or abetalipoproteinemia, treat with vitamin E supplementation.

Ataxia with vitamin B-12 deficiency: Treat with vitamin B-12 supplementation.

Ataxia with coenzyme Q10 (ubiquinone) deficiency: Treat with coenzyme Q10 supplementation. If patients are diagnosed with ataxia with oculomotor apraxia type 1, also consider treatment with coenzyme Q10 supplementation.

Cerebrotendinous xanthomatosis: Prompt diagnosis is advised in order to initiate treatment; treatment with chenodeoxycholic acid is recommended.

Niemann-Pick disease type C: If the results of clinical investigations suggest Niemann-Pick disease type C, perform diagnostic tests as outlined in these guidelines. Because this is a treatable condition, early diagnosis is important. If Niemann-Pick disease type C is diagnosed, promptly refer patients to a specialist for treatment and management. The recommended treatment in both adult and pediatric patients is miglustat, which is available at specialist centers.

Treatable Ataxias in Children
Glucose transporter 1 deficiency: Treat with a ketogenic diet.
Hypobetalipoproteinemia: The moderate form can be treated by reducing the proportion of fat in the patient’s diet and with vitamin E supplementation.

Hartnup disease: Consider treatment with nicotinamide or with a tryptophan-rich diet. Advise patients on a high-protein diet, sunlight protection, and avoiding photosensitizing drugs.

Biotinidase deficiency: Treat with biotin.

Pyruvate deficiency: Consider thiamine, carnitine, or lipoic acid, and advise a ketogenic diet.

Structural disorders: If ataxia is attributable to structural causes, referral for neurosurgical treatment can be recommended.

This information is taken from: Diagnosis and Treatment of Progressive Ataxias Clinical Practice Guidelines (2019) – Medscape – Mar 26, 2019.

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shaheenmoin

I am a Professor of Medicine and a Nephrologist. Having served in the Army Medical College, Pakistan Army for 27 years I eventually became the Dean and Principal of the Bahria University Medical and Dental College Karachi from where I retired in 2016. My passion is teaching and mentoring young doctors. I am associated with the College of Physicians and Surgeons Pakistan as a Fellow and an examiner. I find that many young doctors make mistakes because they do not understand how they should answer questions; basically they do not understand why a question is being asked. My aim is to help them process the information they acquire as part of their education to answer questions, pass examinations and to best take care of patients without supervision of a consultant. Read my blog, interact and ask questions so that I can help you more.

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