Transient ischaemic attack – not such a simple diagnosis

Transient ischaemic attacks (TIA) are one of the most common presentations of neurological symptoms. This, however, does not equate to TIA being one of the easiest to diagnose. This is explored by Nadarajan et al in February’s issue of Practical Neurology (Nadarajan, Perry, & Johnson, 2014). This review expertly emphasises the importance of distinguishing between TIAs and other potential mimics, such as migrainous aura, seizures and syncopal episodes. Other less common TIA mimics and unusual presentations of TIAs are also discussed; whilst these are come across more infrequently, their characteristic presentations and the potentially grave consequences of misdiagnosis underlines their importance. This group will therefore be further discussed in this article.

Cerebral amyloid angiopathy and amyloid spells

Case report 1 – Amyloid “spells” trouble (Charidimou, Law, Werring, 2012)

A previously well 74-year-old man presented to his local hospital, with a history of three episodes of paraesthesia over 2 days. The paraesthesia began in the ulnar fingers of his left hand, and within 2 min had migrated up his arm into his neck, mouth, and tongue, then faded within 1 min. He had no facial droop or visual or language disturbance. He had a medical history of hypercholesterolaemia and hypertension, and was an ex-smoker. CT of the head showed no evidence of acute infarction or haemorrhage. The episodes were diagnosed as transient ischaemic attacks and he was given aspirin, dipyridamole, and simvastatin. He had several further similar attacks over the next few months.

6 months later he was admitted to our stroke unit after waking with left-sided weakness affecting his leg more than his arm. On examination his blood pressure was 144/86; and he had a regular pulse rate of 72 beats per min. His cranial nerves were normal. There was a mild left hemiparesis but reflexes were symmetrical with downgoing plantar reflexes and no sensory deficits. An urgent CT of the brain showed an acute right frontal- parietal intracerebral haemorrhage.

The case highlights the difficulties in TIA diagnosis and the potentially grave consequences of misdiagnosis. Despite the vascular risk factors, the history of migrating paraesthesia should perhaps have brought into question the diagnosis of TIA - one typically expects a TIA to cause negative symptoms, maximal at onset. However, cerebral amyloid angiopathy (CAA) as a cause of such episodes is an under-recognised phenomenon.

CAA describes to process by which small and medium sized arteries, arterioles and capillaries of the brain are affected by a gradual accumulation of Aβ amyloid. This results in thickening of their walls, with loss of smooth muscle, reduced compliance, fibrinoid necrosis and microaneurysm formation (Charidimou, Gang, Werring, 2012). Together, these changes make the vessels more fragile and prone to haemorrhage. Whilst CAA was initially thought to be a rare cause of intra-cerebral haemorrhage, it is now recognised that 20-40% of the non-demented elderly and 40-60% of the demented elderly have some degree of CAA, and that it is second only to hypertensive arteriopathy as a cause of intra-cerebral haemorrhage (Charidimou, Gang, & Werring, 2012). 

Besides haemorrhage, the second most common presentation of CAA is with transient neurological symptoms – so called TIA-like episodes, or amyloid spells. These typically manifest as recurrent stereotyped episodes of migratory symptoms, which may be positive or negative – typically paraesthesia, limb shaking, weakness or visual disturbance (Charidimou et al, 2012). They generally last less than 10 minutes, maximally 30.

Definitive diagnosis of CAA requires histology, but features recognisable on MRI provide good biomarkers of disease. The microaneurysms lead to cerebral microbleeds, and the deposition of blood in the subarachnoid space leads to cerebral superficial siderosis (Charidimou & Werring, 2013). The latter is revealed with susceptibility-weighted or gradient echo imaging, and is found more commonly in patients with CAA presenting with transient neurological symptoms than those without such episodes. The neuroimaging features can also often be correlated anatomically with the site of the symptoms, lending support to the theory that the microbleeds or superficial siderosis bring about the transient episodes via focal seizures or cortical spreading depression (Charidimou, Gang, & Werring, 2012).

One of the most important findings from research into CAA is that transient neurological symptoms often precede symptomatic lobar intra-cerebral haemorrhages (Charidimou, Gang, & Werring, 2012). This may relate to the transient neurological symptoms being a marker of more severe CAA. As highlighted in the above case, this risk may be exaggerated by misdiagnosis and anti-platelets medication (Charidimou, Law, Werring, 2012). When managing patients presenting with TIA-like episodes, but with uncharacteristic features such as migrating and/or positive symptoms, the suggestion may therefore be that one should have a low threshold for MRI, including susceptibility weighted imaging. In the presence of cerebral microbleeds or cerebral superficial siderosis, it may be prudent to stop or avoid anti-platelet medication.

Charidimou, Gang, & Werring. (2012) - susceptibility-weighted imaging highlighting the key findings of cerebral amyloid angiopathy: cerebral superficial siderosis (green arrowhead), cerebral microbleeds (circled) and cortical subarachnoid haemorrhage (arrow)

Limb-shaking TIA

Case report 2 - Limb-Shaking Transient Ischemic Attack (Siniscalchi, 2012)

A 61-year-old man with a medical history of moderate hypertension well-treated with Enalapril comes under our observation for rhythmic jerky movements of his left limb. These episodes, without loss of awareness, would occur at 4–5 Hz, each lasting for 1-2 mins, and taking place about once per month for the past four months, precipitated by standing up and extending the neck. The family history was negative.

There was no history of alcohol, drug abuse, or episodes of syncope. Neurological examination was normal and no orthostatic hypotension was documented. The electroencephalography (EEG) test showed right temporal slow activity, without epileptiform features. 

Limb-shaking TIAs are known to occur in patients with carotid or middle cerebral artery stenosis causing to hemispheric hypoperfusion (Nadarajan, Perry, & Johnson, 2014) (Nedelmann, Kolbe, & Angermueller, 2011). As in the above case, they typically manifest as brief attacks of involuntary jerking of the arm or leg, and may be precipitated by activities that further reduce perfusion, such as standing, exercise, coughing, eating, hyperextension of the neck, antihypertensive medication or moving from cold to warm environments (Persoon, Kappelle, & Klijn, 2010). The main differential is that of a focal motor seizure, with distinguishing features including the absence of a tonic phase or Jacksonian march (Nadarajan, Perry, & Johnson, 2014). EEG recordings, when obtained, also fail to demonstrate seizure activity, often instead showing contralateral slowing, typical of hypoperfusion (Siniscalchi, 2012). Transcranial doppler studies can demonstrate a lack of CO2-reactivity, a sign of hypoperfusion – normal autoreactive cerebral vasculature will dilate in response to increased CO2, but in the presence of hypoperfusion they are already maximally dilated, and this will not occur (Persoon, Kappelle, & Klijn, 2010). 

Movement disorders such as hemidystonia or hemiballismus may occur in basal ganglia or subthalamic nuclei infarcts, but in the case of limb-shaking TIAs, the movements are thought to occur due to transient cerebral ischaemia, rather than infarction. Indeed, there are many reported cases of the episodes resolving following revascularisation surgery (Kouvelos, Nassis, & Papa, 2012) – the potential of such techniques again highlights the importance of accurate diagnosis.

Nedelmann, Kolbe, & Angermueller. (2011) - video of limb-shaking symptoms experienced due to haemodynamic TIA following change in posture from laying to sitting.

Capsular warning syndrome

Case report 3 – Capsular warning syndrome (Zhou et al, 2014)

A 63-year-old man with a history of hypertension was seen with recurrent episodes of left hemiparesis and dysarthria lasting 10-15 minutes in the emergency room. His blood pressure was 136/94 mmHg. Neurological examination on admission was unremarkable. Treatment with antithrombotic medication (aspirin 200 mg) and hydration was given immediately. During the first 48 hours of hospitalisation he experienced 9 further episodes of left hemiparesis, left facial palsy and dysarthria lasting 13 to 36 minutes. His neurologic status fluctuated between 5 and 11 on the National Institutes of Health Stroke Scale (NIHSS), with failure to recover fully from the last episode leaving a persistent left mild hemiparesis and facial palsy (NIHSS 3). Brain MRI showed an acute infarct on right putamen with rostral extension to the corona radiata.

Capsular warning syndrome is a particular manifestation of crescendo TIA – a series of recurrent episodes occurring over days to weeks (Nadarajan, Perry, & Johnson, 2014). Originally described by Donnan (Donnan, O'Malley, & Quang, 1993), it was attributed to disease of a single perforator artery, postulating that such disease allowed haemodynamic changes to result in intermittent ischaemia. The presentation was with motor or sensory involvement of the face, arm or leg, without cortical symptoms. A similar presentation may also be caused by basilar branch disease, leading to paramedian pontine ischaemia. This has been referred to as the pontine warning syndrome - ophthalmoplegia may be noted as an additional feature in such cases (Farrar & Donnan, 1993) (Saposnik, 2008).

The importance of recognising capsular warning syndrome is that it has been shown to represent a very high risk of subsequent infarction - quoted values range from 40-60%, and are consistently shown to be far higher than any other presentation of TIA (Donnan, O'Malley, & Quang, 1993) (Paul, Simoni, Chandratheva, & Rothwell, 2012). Given such high risks, various treatments have been tried, from typical anti-platelet therapy and thrombolysis to therapeutic hypertension (Vavanco-Hidalgo, Rodriguez-Campello, & Ois, 2008) (Fahey, Alberts, & Bernstein, 2005). All have been shown to be of benefit in case reports, but the absence of sufficiently powered studies comparing such techniques means that there is currently little evidence with which to guide management. A prospective study showed a trend towards reduced incidence of infarction with anti-platelet agents, but in the very small sample, significance was not reached (Paul, Simoni, Chandratheva, & Rothwell, 2012). 

Further debate has recently been thrown into the topic of capsular warning syndrome – reports of diffusion-weighted imaging confirming capsular lacunar infarction during the ongoing symptom fluctuations has called into question the hypothesis of intermittent ischaemia (Springer & Labovitz, 2013). The authors suggest that rather than due to intermittent ischaemia, the fluctuations are instead due to the initial attempts at motor plasticity following infarction, as compensatory networks are recruited into the task of motor control. With other reports suggesting patients have presented before evidence of infarction, the debate is likely to continue (Vavanco-Hidalgo, Rodriguez-Campello, & Ois, 2008).

Paul, Simoni, Chandratheva, & Rothwell. (2012) - risk of subsequent infarction following capsular warning syndrome compared to other TIAs

Conclusion

Patients presenting with transient neurological symptoms continue to be a diagnostic challenge.  As the symptoms have often resolved by the time medical attention is sought, expert interpretation of the patient’s history is crucial. Although the main differentials to be distinguished include migrainous auras, seizures and syncope, the other less common presentations must also be considered. As discussed in this article, awareness of these should allow the clinician to avoid doing harm (such as using anti-platelets agents in amyloid spells), and to instigate timely investigations and therapies (such capsular warning syndrome requiring antiplatelet agents or thrombolysis, or limb-shaking TIA that may be amiable to vascular interventions).

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