Ataxia Flashcards
Spinocerebellar Ataxias
Spinocerebellar ataxias are a group of autosomal dominant disorders which are associated with the progressive development of ataxic features such as gait disturbance, nystagmus and tremor. The majority of affected patients develop symptoms within the 3rd and 4th decade.
Spinocerebellar Ataxis - Example Question
A 36 year old male presents to your outpatient clinic with a progressive history over the past 5 years of increasing, progressive ‘clumsiness’. His work colleagues had a long running joke with him that he is poorly coordinated for about the past five years but in recent weeks, he has noticed that he is unable to write legibly or even hold a key still using either hand to open a door. He denies any recent weight loss of night sweats, is otherwise healthy with no other past medical history. He is a lifelong non-smoker with a minimal alcohol history and lives with his wife and 2 children.
On examination, his cranial nerves were unremarkable except for mild multidirectional nystagmus at primary gaze. Fundoscopy was normal. Limb examination revealed significant impairment of finger-nose and heel-shin testing. His gait, tone, power, sensation and reflexes were normal with downgoing plantars. A brief mini-mental state examination scored 30/30. An MRI head is awaited. His blood tests are as below:
Hb 15.8 g/dl
Platelets 323 * 109/l
WBC 6.5 * 109/l
Na+ 141 mmol/l K+ 4.9 mmol/l Urea 6.6 mmol/l Creatinine 85 µmol/l CRP 2 mg/l Creatine kinase 223 IU/l (50-335) TSH 3.3 mu/l Free T4 17 nmol/l HIV negative Anti-neuronal antibodies negative
Which investigation is likely to yield the diagnosis?
> Neurogenetics testing CT chest, abdomen, pelvis Vitamin B12 and folate levels Lumbar puncture for cerebrospinal fluid including 14-3-3 and S100 Anti-GQ1b antibodies
There appears to be a chronic onset syndrome of pure ataxia, without systemic features or cognitive impairment, nor history of alcohol excess. The likely diagnosis is one of spinocerebellar ataxias (SCA), in particular one of the classified ‘type III’ syndrome such as SCA6, an adult onset cerebellar ataxia diagnosed by neurogenetic testing.
It is important to rule out key differential diagnoses however: patients with acute onset cerebellar syndrome should be considered for Miller-Fisher syndrome, a post-viral variant of Guillain Barre syndrome resulting in a triad of ophthalmoplegia, ataxia and areflexia, commonly after gastrointestinal infections, diagnosed with positive anti GQ1b antibodies. The time course for this illness over 5 years makes Miller-Fisher unlikely.
A subacute course of weeks and small number of months should alert you to possible prion disease such as Creutzfeld Jakob disease (CJD) and a paraneoplastic syndrome. The former typically presents with rapid cognitive decline and myoclonus, classically with MRI features (pulvinar sign, cortical ribboning), CSF features (14-3-3, S100, real-time QUIC) and EEG features (periodic spiking). The latter can present years before a solid tumour is identified on structural imaging with positive anti-neuronal antibodies, resulting in progressive symptoms as the cerebellum degenerate over months. Due to the low sensitivity of anti-neuronal antibodies, a negative result does not necessarily rule out paraneoplastic syndrome but such a long time course of 5 years would be unusual. The likelihood of identifying a significant mass on cross sectional CT imaging is low.
Lastly, the lack of a alcohol or gastrointestinal history makes cerebellar degeneration due to vitamin deficiency very unlikely. As a result, neurogenetics testing for SCA is most likely to yield the underlying diagnosis.
Differentials of Cerebellar Syndrome
Patients with acute onset cerebellar syndrome should be considered for
- Miller-Fisher syndrome, a post-viral variant of Guillain Barre syndrome resulting in a triad of ophthalmoplegia, ataxia and areflexia, commonly after gastrointestinal infections, diagnosed with positive anti GQ1b antibodies.
Patients with a subacute course of weeks and small number of months should alert you to:
- Possible prion disease such as Creutzfeld Jakob disease (CJD) and a paraneoplastic syndrome. The former typically presents with rapid cognitive decline and myoclonus, classically with MRI features (pulvinar sign, cortical ribboning), CSF features (14-3-3, S100, real-time QUIC) and EEG features (periodic spiking).
The latter can present years before a solid tumour is identified on structural imaging with positive anti-neuronal antibodies, resulting in progressive symptoms as the cerebellum degenerate over months. Due to the low sensitivity of anti-neuronal antibodies, a negative result does not necessarily rule out paraneoplastic syndrome but a long time course of 5 years e.g. that seen in Spinocerebellar Ataxia would be unusual. The likelihood of identifying a significant mass on cross sectional CT imaging is low.
Finally assess patient for alcohol and GI history to consider cerebellar degeneration due to vitamin deficiency
Friedrich’s Ataxia
Friedrichs ataxia is an autosomal recessive inherited condition in which there is progressive ataxia, dysarthria, loss of proprioceptive and vibration sensation and weakness.
Friedrich’s Ataxia: Example Question
A 23 year old investment banking intern presents to the urgent care centre complaining of progressive unsteadiness on walking over the past 6 months. He has no past medical history except type 2 diabetes, which is diet controlled, diagnosed one year ago. He has no family history of any diseases. He has been working very long hours for the past 2 years and reports high levels of stress at work, coupled a culture of ‘binge-drinking’ to team bond after work. Over the past 3 months, he has noticed a lack of articulation with his speech, which he assumed was secondary to alcohol. He estimates he drinks up to 30 units of alcohol a week. On examination, his cardiovascular, respiratory and abdominal systems are unremarkable. His finger-nose test is impaired bilaterally and is unable to tandem walk. He denies any neck stiffness or headache. He has a full range of eye movements. He has absent reflexes in his lower limbs and upgoing plantars bilaterally. Which investigation will provide the definitive diagnosis?
MRI head with gadolinium contrast CT angiography including posterior vessels Lumbar puncture > Serum genetic testing Muscle biopsy
The patient describes cerebellar signs of dysarthria, poor coordination and ataxia, in addition to absent ankle jerks and upgoing plantars, presenting at an early age with progressive symptoms. Friedrichs ataxia and other spinocerebellar ataxias must be considered. A diagnosis of type 2 diabetes is odd in such a young patient. However, up to 1/3 of patients with Friedrichs ataxia experience impaired glucose tolerance or diabetes mellitus. These patients often present with cardiomyopathy as well, causing arrhythmias and heart failures.
This patient presents slightly late, most patients have symptoms by childhood. Up to 90% present by 25 years old1. It is often assumed that spinocerebellar ataxias, in this case an autosomal recessive one, must be accompanied by a family history. In 40% of Friedrichs ataxias, there is no positive family history at all1.
Diagnosis is by serum genetic testing of the GAA trinucleotide repeat. Treatment is limited but involves a multidisciplinary team of neurologists, cardiologists and endocrinologists. There are theories that iron chelation is important in Friedrichs ataxia but these are yet to be proven in large scale studies2.
Friedrich’s Ataxia
Friedreich’s ataxia is the most common of the early-onset hereditary ataxias. It is an autosomal recessive, trinucleotide repeat disorder characterised by a GAA repeat in the X25 gene on chromosome 9 (frataxin). Friedreich’s ataxia is unusual amongst trinucleotide repeat disorders in not demonstrating the phenomenon of anticipation.
Friedrich’s Ataxia - Features
The typical age of onset is 10-15 years old. Gait ataxia and kyphoscoliosis are the most common presenting features.
Neurological features absent ankle jerks/extensor plantars cerebellar ataxia optic atrophy spinocerebellar tract degeneration
Other features
hypertrophic obstructive cardiomyopathy (90%, most common cause of death)
diabetes mellitus (10-20%)
high-arched palate
Friedrich’s Ataxia vs Ataxia Telangiectasia
BOTH:
Autosomal Recessive
Cerebellar Ataxia
Onset in Childhood
Friedrich’s Ataxia:
- Trinucleotide repeat disorder but no anticipation
- Optic atrophy
- Kyphoscoliosis
- HOCM
- Onset 10-15
- DM
Ataxic Telangiectasia:
- Telangiectasia - Spider angiomas
- IgA deficiency > Recurrent infections
- Increased risk of lymphoma and leukaemia
- Onset 1-5 years
Note in particular how ataxic telangiectasia tends to present much earlier, often at the age of 1-2 years
Spinocerebellar Ataxia Presentation
Presentation = chronic onset syndrome of pure ataxia, without systemic features or cognitive impairment, nor history of alcohol excess.
> Likely diagnosis is one of spinocerebellar ataxias (SCA), in particular one of the classified ‘type III’ syndrome such as SCA6, an adult onset cerebellar ataxia diagnosed by neurogenetic testing.
Friedrich’s Ataxia
Presentation = Cerebellar signs of dysarthria, poor coordination and ataxia, in addition to absent ankle jerks and upgoing plantars, presenting at an early age with progressive symptoms.
Friedrichs ataxia and other spinocerebellar ataxias must be considered.
Up to 1/3 of patients with Friedrichs ataxia experience impaired glucose tolerance or diabetes mellitus. These patients often present with cardiomyopathy as well, causing arrhythmias and heart failures.
Patients can present slightly late but most patients have symptoms by childhood. Up to 90% present by 25 years old.
It is often assumed that spinocerebellar ataxia must be accompanied by a family history. In 40% of Friedrichs ataxias, there is no positive family history at all.
Diagnosis is by serum genetic testing of the GAA trinucleotide repeat.
Treatment is limited but involves a multidisciplinary team of neurologists, cardiologists and endocrinologists. There are theories that iron chelation is important in Friedrichs ataxia but these are yet to be proven in large scale studies.
