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A 70-year-old woman presented with a 2-month history of gradually progressive unsteadiness. She started to fall a few weeks before assessment and was holding furniture to balance herself. She complained of recent memory loss and constipation. Additionally she was being investigated for ‘scarring on the lung’ found on a chest X-ray. She took no medications and drank no alcohol. She had no relevant family history. On examination, there was horizontal nystagmus and dysarthria (staccato-type). She had moderate gait and limb ataxia. Romberg's test was negative. Her ankle jerks were absent but sensation was intact to all modalities. We found pitting oedema below the knees. An MR scan of the brain was normal.
Question 1
How would you classify her type of ataxia?
Comment
The eye movements, speech and limb findings suggest cerebellar ataxia. While the ankle jerks were absent, her distal sensation and her Romberg's test were normal, making it unlikely that there was a concomitant sensory ataxia. The bilateral cranial nerve and limb findings suggest a generalised cerebellar process. The speed of progression is in the slower end of the subacute category (weeks to months).
This helps to exclude several common causes of cerebellar ataxia in older patients. Strokes tend to be of sudden onset and unilateral. Degenerative conditions tend to be slower and associated with other neurological findings on examination (eg, multiple system atrophy). Her age of onset and negative family history make a genetic cause less likely.
Her cerebellar ataxia could be classified as subacute, generalised and late-onset.
Question 2
What are the main causes of a subacute cerebellar ataxia?
Comment
There is a relatively short list of conditions that can cause subacute cerebellar ataxia (table 1).
Paraneoplastic cerebellar degeneration is a possibility. This tends to progress more rapidly over weeks. Patients usually become bed-bound due to ongoing antibody-mediated destruction of Purkinje cells. This is likely to be caused by cross-reacting cellular and humoral immune responses. This patient, while moderately ataxic, had not progressed to this extent. However, the chest X-ray abnormality raised the suspicion of lung cancer. The most common antibody found is anti-Yo. Associated cancers include small cell lung, breast, ovarian and Hodgkin's lymphoma. Anti-Tr presents more slowly. The MR scan of brain is often normal in the early stages, but by 3 months into the course you might expect to see some atrophy. Paraneoplastic disorders can precede the detection of cancer. In paraneoplastic cerebellar degeneration, this can be by up to 4 years.
Other antibody related conditions can present with subacute ataxia. In Miller Fisher syndrome (a variant of acute inflammatory demyelinating polyradiculoneuropathy) progression is usually over 1–2 weeks. The triad of ophthalmoplegia, widespread areflexia and ataxia helps the clinical diagnosis. This patient's course was too slow and she had not developed these other features. The serum anti-GQ1b ganglioside antibody concentration is commonly elevated in this condition.
Creutzfeldt-Jakob disease also tends to be more aggressive. You would also expect other features to have emerged by this stage, in particular dementia, myoclonus or parkinsonism. In addition, the MR scan appearance is usually abnormal by this stage.
Structural causes (as mentioned in the table) are uncommon and would be associated with other signs. The MR scan of brain would not be normal.
Medication-induced ataxia may occur with antiepileptic medication (particularly phenytoin, carbamazepine and gabapentin), metronidazole, amiodarone, pregabalin and some chemotherapy drugs. This is more commonly chronic, along with alcohol toxicity.1
Strokes and demyelination are relatively common causes of cerebellar dysfunction, but tend to be acute in onset.
Question 3
Do the associated clinical features provide any diagnostic clues?
Comment
In this case, it was the additional systemic symptoms that made the diagnosis apparent. The combination of cognitive decline, constipation and peripheral oedema suggested hypothyroidism. Hypothyroidism is most commonly autoimmune and due to antithyroid antibodies. It can also follow treatment for hyperthyroidism. It is more common in women.
Common symptoms include weight gain, sensitivity to cold, constipation and mental slowing. Clinical signs can include periorbital oedema, peripheral oedema, bradycardia and thinned hair. Ankle jerks are often described as being slow-relaxing. Some advocate testing these with the patient kneeling on a chair.
Patients with hypothyroidism can present with encephalopathy and coma that is potentially fatal. It is crucial to check thyroid function in patients with encephalopathy of unknown cause, given that treatment is available.
Question 4
Her serum thyroid-stimulating hormone (TSH) concentration was 16.4 mU/L (0.4–5.0) and serum-free T4 was 11.9 pmol/L (10–24). How do these results help with the diagnosis? What additional blood tests could you request?
Comment
The biochemical findings of an elevated TSH (>10 mU/L) with a low-normal free T4 suggests primary hypothyroidism. The reduced hormonal secretion from the thyroid gland causes a compensatory rise in pituitary TSH secretion. Thyroid peroxidase antibodies were markedly positive with a titre of 903 (normal range 0–60), consistent with an autoimmune cause. The serum-free T3 was 4.7 pmol/L (4.0–8.3).
In symptomatic hypothyroidism, the serum TSH can be only slightly raised and the plasma T4 and T3 can be within the normal ranges. It is important to interpret this in the clinical context.
A few weeks after starting treatment with thyroxine, her ataxia, constipation, mental slowness and peripheral oedema had resolved. Repeat thyroid function testing was normal: her TSH was 3.6 mU/L (0.4–5.0), free T4 was 19.5 pmol/L (10.0–22.0) and T3 was 5.1 nmol/L (1.07–3.18).
Question 5
What neurological conditions are associated with hypothyroidism?
Autoimmune thyroiditis causes over 90% of cases of hypothyroidism in iodine-depleted areas (such as the UK) and is one of the most common autoimmune diseases in Western countries.
Hypothyroidism can affect almost every part of the nervous system (box 1). It is a well recognised mimic of myasthenia gravis and vice versa. Hypothyroidism and myasthenia gravis can coexist and it is important to consider both in the differential of patients with proximal weakness. Respiratory muscle failure is more likely due to myasthenia gravis.
Neurological conditions associated with hypothyroidism
Myasthenia gravis
Headache
Carpal tunnel syndrome
Proximal myopathy
Peripheral neuropathy
Polyradiculopathy
Dysphonia
Encephalopathy, seizures and stroke-like events
Coma
Pseudomyotonia
Ataxia
Hypothyroid periodic paralysis
Congenital hypothyroidism
There is an association between high serum titres of antithyroid peroxidase antibody and encephalopathy. This is sometimes referred to as ‘steroid-responsive encephalopathy associated with autoimmune thyroiditis’, previously known as Hashimoto's encephalopathy. It is a controversial diagnosis, with no clear evidence that thyroid antibodies are pathogenic. However, there is an association between antibody-mediated hypothyroidism and encephalopathy. In addition to confusion, patients can present with stroke-like events, seizures, cognitive decline, neuropsychiatric symptoms and myoclonus. The electroencephalogram can show generalised slowing, frontal rhythmical slowing and triphasic waves.2
If hypothyroidism is left untreated, myxoedema coma can occur. It is important always to check thyroid function in a patient with an encephalopathy or coma of uncertain cause. Myxoedema is often precipitated by physiological stress such as infection. Confusion, hypothermia, hyponatraemia and respiratory acidosis can occur.
Hypothyroidism is associated with cognitive and motor impairments. Patients with autoimmune thyroiditis are at increased risk of cardiovascular events, with a 20% increased risk of coronary heart disease. Autoimmune thyroiditis is also a minor risk factor for stroke. In a study of 34 907 patients with autoimmune thyroiditis, the relative risk of stroke was 1.1 (95% CI 1.01–1.2).3
Carpal tunnel syndrome and peripheral neuropathy are commonly associated with hypothyroidism. Patients may develop muscle stiffness and cramps associated with proximal weakness. Some patients have a slow relaxation of muscle after contraction (pseudomyotonia), reflected in slow-relaxing ankle jerks.
Congenital hypothyroidism due to iodine deficiency (cretinism) can cause mental retardation, deaf mutism, strabismus, spastic diplegia and rigidity.
For further reading about the neurological aspects of thyroid dysfunction, please refer to the excellent review by Mistry et al.4
Box 1 provides a list of the neurological conditions associated with hypothyroidism.
Practice points
Ataxia can develop in up to a third of patients with hypothyroidism.
It should be considered in the differential of subacute-onset cerebellar ataxia, along with antibody-mediated, metabolic, infective (prion disease), toxic and structural causes.
Thyroid hormones have an ongoing role in cerebellar neuronal function.
Hypothyroid-induced cerebellar ataxia is usually reversible with thyroid hormone replacement.
Discussion
Hypothyroidism is reasonably common but patients with this are rarely referred primarily to neurologists. One series found that 64% of patients with hypothyroidism complained of neuropathic symptoms.4 Ataxia is an unusual presenting complaint in hypothyroidism, but can develop in up to a third of patients. In most cases the ataxia is reversible but there are several reported cases of progressive cerebellar degeneration.5 It is important to recognise the systemic features of thyroid disorders, which proved the most useful differentiating feature in this case.
Thyroid hormones regulate myelination, cell proliferation, gliogenesis and protein synthesis. Hypothyroidism affects the establishment of neuronal connections.6
The major source of T3 in the brain is derived from type II iodothyronine deiodinase (DIO2), which catalyses the generation of T3 from T4.7 Thyroid hormone regulates the binding of DIO2 vesicles to F-actin. Myosin V is thought to participate in vesicle trafficking in the brain, acting as a molecular motor. It is abundant in nerve terminals and associates with synaptic vesicles.7 Myosin V plays a major role in the thyroid hormone-dependent, actin-based endocytosis of DIO2, and therefore has a crucial role in thyroid hormone regulation within the central nervous system.
Thyroid hormones have an ongoing role in adult cerebellar neurone proliferation and maturation. In hypothyroidism, cerebellar signs usually develop gradually over weeks to months.8
Cremer et al published a series on 24 patients with hypothyroidism and cerebellar ataxia at the Mayo Clinic between 1958 and 1966. Their average age was 61.6 (40–76) years. The symptoms of ataxia were usually preceded by other symptoms of hypothyroidism (as in our case) but occasionally were the first manifestation. All 24 patients had an ataxic gait but only 10 had definite limb ataxia. Only one patient had dysarthria. There was a mixture of suspected causes, including presumed antibody-mediated and other potentially non-antibody-mediated causes, for example, pituitary adenoma, Sheehan's syndrome, following neck radiotherapy. All patients (apart from one lost to follow-up) responded to thyroid hormone replacement.9 This suggests that a deficiency of thyroid hormone can induce cerebellar dysfunction independent of an immunological process.
Hypothyroidism can present with a broad range of neurological signs and symptoms. It is therefore important to consider the diagnosis in presentations of ataxia, peripheral neuropathy, myasthenia gravis or coma of uncertain cause. Routine thyroid function testing should be performed in the neurology clinic setting for patients with undifferentiated presentations.
Footnotes
Contributors DB and LW: writing of first draft and subsequent revisions.
Competing interests None declared.
Patient consent Obtained.
Provenance and peer review Not commissioned; externally peer reviewed. This paper was reviewed by Martin Turner, Oxford, UK.
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