Clinical presentation of strokes confined to the insula: a systematic review of literature

The literature search identified 70 papers, and 37 were selected after screening titles and abstracts (Supplementary material). Figure I (Supplementary material) shows a “Prisma Diagram” [17] of studies included and excluded. Out of the 37 retrieved, 9 studies were excluded because they were not focused on insular lesions, 2 because they were reviews and 1 because it reported insular stroke data without focusing on clinical manifestations. Thus, after reviewing the full text, we included 25 papers. Supplementary Table I shows all included studies on insular stroke [10‐13, 15, 18‐37].

We found 49 patients (59.7 ± 15.5 years old, 24 males) from literature with strokes confined to the insula (Supplementary Table I) [10‐13, 15, 18‐37]. Figure 2 shows the distribution of aetiology in all patients and with the site of the lesion.

Supplementary Table II and Fig. 3 describe the symptoms of patients with IS, their frequency and relationship with the site and side of the lesion. Motor and sensory deficits, dysarthria, aphasia, vestibular-like syndrome, dysphagia, awareness deficits, gustatory disturbances, cardiovascular alteration and dysautonomia and neuropsychiatric disturbances were the most frequent symptoms. Further unusual symptoms were reported in a minority of cases.

We found 9 patients (57.8 ± 12.1 years old, 5 males) with strokes in the AIC (18%), 20 patients (57.6 ± 18.6 years old, 8 males) in the PIC (41%) and 20 patients (62.2±13.6 years old, 12 males) in the TIC (41%). Supplementary Table III and Fig. 3a report symptoms and frequency with the site of the lesion.

We found 23 patients with strokes in the right (47%) and 26 in the left (53%) insular cortex. Supplementary Table IV and Fig. 3b report symptoms and frequency in relation to the side of the lesion.

The appearance of symptoms related to insular dysfunction has been the object of several studies in patients affected by stroke from the late 1990 to the last 20 years [10‐15]. In one study, 4 cases of IS were reported among 4800 (0.08%) patients with first acute stroke [10]; the authors concluded that clinical presentations of insular stroke fall into five principal clinical presentations: somatosensory, gustatory, vestibular-like, cardiovascular and neuropsychological syndromes. In 2004, a series was published of 11 patients among 2600 patients (0.4%) with first-ever ischemic stroke restricted to subinsular territory between 1999 through 2002 [12]. In this paper, based on a larger sample population, some additional symptoms appeared such as dysphagia, transcortical motor aphasia, dysarthria, neglect and apathy. Subsequently, a retrospective multicentric analysis identified 7 more patients with IS, reporting a similar constellation of symptoms without new features [15]. More recently, a paper reported a higher incidence of IS, describing 10 patients with PIC out a total population of 475 [14]. In this paper, no vestibular-like symptoms were not described.

Pure insular stroke is very rare; hence, no epidemiological studies have been performed to date. The insula is supplied from the M2 segment of the MCA. Embolic occlusion of M2 or its branches is the main cause of IS, but the exact aetiology and the origin of embolism are debated. From published case series and case reports, the aetiology is usually unknown or not reported (Fig. 2). Large-artery disease seems to be the most prevalent aetiology, especially in the context of larger lesions, followed by cardioembolism (Fig. 2) [12].

In the more recent past, reporting on insular strokes has become more frequent, probably because of successful recanalization rates through thrombolysis and thrombectomy with the understanding that successful thrombolysis or thrombectomy has the potential to fragment the acute occlusive clot, which can migrate downstream, thus occluding smaller branches, such as insular feeders [8]. Finally, the use of sophisticated neuroimaging techniques and high field MRI has allowed a more accurate definition of the insular region and the description of strokes confined to this small territory.

A combination of somatosensory and speech disturbances usually suggests a complete MCA stroke, but the co-occurrence of rarer symptoms could, instead, suggest a more focal involvement of the insula (Supplementary material) [4, 9]. Although most patients with IS present with symptoms that can be grouped into a small number of symptom, cluster presentations are also described with a wider array of symptoms.

Motor deficits are the most common symptoms encountered in IS, ranging from facial weakness to hemiplegia [11, 12, 15, 24, 32‐34, 36]. Hemiparesis is the typical presentation, followed by a facio-brachial pattern of weakness (Supplementary Table II). Motor deficits more often occur in association with other symptoms and are more frequent in lesions involving both the AIC and PIC [11, 12, 15, 24, 32‐34, 36]. In fact, weakness was reported in 53% of patients with IS. Moreover, among patients who presented motor deficits, 61% presented a lesion involving the whole insula, 23% in the PIC and only 15% in the AIC (Supplementary Table II).

Somatosensory deficits are very common following IS, especially in lesions of the PIC and with more extended lesions (Supplementary Table II, Fig. 3); they range from difficulties in controlling directions of movements to more variable deficits in vibration sense, astereognosis and dysesthesia with positive sensations in absence of stimuli [10, 12, 13, 15, 19, 23, 26, 28, 32, 37]. Sensory symptoms appear to be transient, usually last a few days and then subsiding over the following weeks, but can persist and become chronic. Mild deficits or numbness in the contralateral upper limb are the most frequent sensory complaint and are often extended to involve the contralateral body and face. Rarely, IS may cause dissociated sensory deficits involving a single modality [12, 26, 28] or non-specific sensory complaints [12, 15].

Dysarthria is another common manifestation in patients affected by IS [10‐12, 15, 23, 24, 32, 33, 35, 36]. It appears with similar rates in both right and left IS and is more frequent in bigger lesions and PIC strokes. Most reports do not quantify the severity of dysarthria, and there is only one report of complete anarthria in a patient with bilateral ageusia and dysphagia [23].

Aphasia is a typical finding of dominant hemisphere IS, being reported in 73% of left hemisphere IS [10‐12, 15, 18, 24, 26, 29, 32, 36]. Language deficits are well-reported ranging from a word-finding difficulty with anomia and mild lexical dysgraphia-dyslexia to more severe non-fluent aphasia with altered comprehension; the most common pattern is non-fluent aphasia with anomia but essentially preserved comprehension and repetition [12, 15]. These deficits may be severe-moderate with phonemic paraphasia (42% of aphasic patients with IS) or mild with word-finding difficulty (21%), but they usually recover in a few days with mild or no residual deficits. Apart from a clear lateralization to the left hemisphere, aphasia seems to be more common in PIC IS (Supplementary Table II).

The high prevalence of aphasia after insular stroke is expected, as it is well-known that a dominant perisylvian MCA infarction (including the insula) often produce motor, sensory or global aphasia [38]. Moreover, distinct aphasic syndromes have been reported depending on the insular topography; according to some authors, lesions in the AIC usually cause Broca’s aphasia, whilst the middle gyri and PIC are associated with conduction aphasia and Wernicke’s aphasia [38].

A “vestibular-like syndrome” (VLS) has been reported in 33% of IS, representing the fifth most common symptom of IS in order of frequency after sensory-motor deficits and language impairment (Supplementary Table II, Fig. 3) [10, 12, 15, 19, 20, 29, 35]. Moreover, vertigo can be the only symptom of a stroke confined to the PIC [10, 20]. Despite being reported more often after right IS, there is not a clear lateralization for VLS (Supplementary Table II, IV, Fig. 3). VLS have been reported after direct electrical cortical stimulation, but no left-right differences were observed [1, 2]. Similarly, anatomical studies identified the posterior parietal operculum and the retroinsular region as crucial regions for vestibular processing, but, to our knowledge, a major role of the right (respect to the left) insula has not been reported [1, 2]. This difference, not emerging from direct stimulation, might indicate a reduced recovery potential of the right hemisphere from VLS due to right IS. However, this weak evidence should be confirmed and explored from future studies. Overall, VLS is heterogeneous. Patients may present with isolated “vertigo” or “dizziness” with instability. Occasionally, nystagmus and lateropulsion have been also reported, associated with nausea and vomiting [19]. Former studies described dizziness, vertigo, unsteadiness and gait instability without any abnormality of eye movements or nystagmus [12, 15]. Horizontal nystagmus has been reported as an isolated abnormality in a case of IS [29] and described as a “pseudovestibular neuritis”. Subjective dizziness with ataxia has been described in a patient with AIC stroke [31] and possibly explained as occurring as a result of disconnection between supra- and infratentorial centres of balance and coordination [39].

Dysphagia is a frequent complaint after IS, being experienced in one out of four patients [11, 12, 15, 23]. Sometimes it is described as coughing or hoarseness after ingestion of liquids, or as non-specific dysphagia. These symptoms appear to be transient with a rapid recovery reported [12]. In our review, 80% of dysphagic patients presented with lesions in the AIC or lesions including the TIC. We found no difference in the incidence of dysphagia depending on the side of the lesion. In a recent paper on ischemic stroke patients, dysphagia was correlated with the region of involvement of the insula [40]. In this study, dysphagia was reported in 22% of TIC strokes and in 40% of AIC strokes but in no patients with PIC injury. On the other hand, AIC was impaired in all patients with dysphagia, thus suggesting the AIC as the cortical region tasked with deglutition control.

Hemi-spatial and awareness deficits are well-described symptoms resulting from damage to the right hemisphere, and they have also been reported after IS [10‐12, 15]. Hemi-spatial neglect is the typical manifestation, with loss of capacity to respond to stimuli contralateral to the lesion [41]; patients may also have the impression of loss of awareness of one side (asomatognosia) or deny ownership of a limb or an entire side of one’s body (somatoparaphrenia) [15]. Also, this kind of disturbances can be associated with transient somatosensory deficits [10, 12, 15]. These deficits are reported more frequently in right-sided IS but are present in only 26% of right IS described in the literature (Supplementary Table II). These data may be an underestimate of the true incidence if screening for spatial deficits after stroke is inadequate [42]. Among patients with hemi-spatial awareness deficits, 57% had injury extended to the whole insula, and 43% had PIC lesions, whilst there are no identified cases with AIC lesions (Supplementary Table II).

Alteration in taste recognition, ranging from heightened taste intensity to bilateral ageusia, is a common feature of IS [10, 12, 13, 15, 23, 26]. Unpleasant taste sensation (parageusia) is, however, uncommon and only reported in a few cases. One patient experienced a persistent flavour of rotten melon after an infarct involving the left AIC [13]. Alteration in food preference (Gourmand syndrome) has not been reported to date [23]. In the literature to date, taste disturbance occurred in 12% of IS but did not lateralise or occur more frequently in any IC pattern of injury. Gustatory disturbanceoccurs more frequently and is more severe after left IS, occurring in 19% of left IS, but only 4% of right IS (Supplementary Table IV); bilateral ageusia was reported in 2 patients after left IS [10, 23] and in one patient after right IS [12]. These reports suggest that the dominant AIC represents a crucial region for the perception of taste. As for hemi-spatial awareness symptoms, gustatory disturbances may well be underreported, because taste assessment is not part of the routine neurological exam.

Neuropsychiatric symptoms have been described in approximatively 10% of patients with IS [12, 32, 34, 35]. Whilst these symptoms, if present, may well significantly influence the outcome of IS, they may be missed or mis-registered because a complete neuropsychiatric assessment is not regularly performed in stroke units [43]. Anergia was reported in patients with strokes involving the right insula [42]. Mood disorders have been reported in two patients following IS: one developed apathy [12], the other complained of emotional flatness and loss of empathy, with increased anxiety and phobia [32]. Impairment in verbal and logical memory has been reported after left and right IS, respectively [43]. Executive function and attention difficulties were also reported in two further cases [34, 35], but studies systematically evaluating psychological profile following IS are not available, to our knowledge.

When psychological symptoms have been recognized in the literature, they have been more frequent after damage in the left insula; for this reason, it has been hypothesized that a disconnection of the dominant insula with the frontal lobe and cingulate cortex may be the origin of NPS [43].

Several cardiovascular disorders have been associated with IS [10, 11, 15, 24, 30, 33, 35]. Arrhythmias are the more common in this category including paroxysmal ventricular tachycardia, atrial flutter, ST abnormalities and ventricular extrasystoles [11, 33, 35]. Hypertensive bursts are also frequently reported [24, 30]. These symptoms may be associated with concomitant cardiac disease, but some authors have considered them an expression of dysautonomia, because they are often associated with hypertensive bursts, light headedness and pallor [44, 45]. More recently, IS has been associated with ST segment abnormalities, high rates of sinus tachycardia and ectopic beats [46]. In particular, right lesions appear to be associated with paroxysmal short-lasting ventricular tachycardia even in the presence of normal results upon cardiological assessment [33] and left-sided lesions with T wave inversion and a left anterior fasciculus block pattern on electrocardiogram in the absence of coronary heart disease or cardiac pathology [24], with atrial flutter and cardiomyopathy [11] and supraventricular and ventricular extrasystoles with short episodes of ventricular tachycardia [35]. Left insular involvement was associated with an increased risk of an adverse cardiac outcome [47]. Also, insular involvement and higher disability at onset were associated with a greater incidence of autonomic dysfunction post-stroke [48]. Furthermore, one report has suggested that insula dysfunction may be a cause of cerebrogenic sudden death [49].

The overall incidence of these symptoms seems to not differ in relation with site and side of the lesion (Supplementary Table II, Fig. 3), but arrhythmias are more frequently described after left IS. Once again, such symptoms probably have an incidence higher than reported, because they may escape routine evaluation and follow-up. A systematic approach to dysautonomia is needed to define the relationship between the insular cortex and these symptoms.

Auditory disturbances have been described in 4 patients with stroke confined to the insula; typically with increased sensitivity to sound. One of these patients described the character of the experienced transient auditory hallucinations as being similar to “videogame” noises [34].

Headache was described in 3 patients with right IS [15, 34]. Finally, there are single cases reporting Horner’s syndrome in IS related to carotid dissection [15], focal seizures following right IS [37] and sexual dysfunction as a result of drop in libido following left PIC stroke [32].

There are no data on long-term follow-up for IS, but outcomes in the cases reported were generally good with the majority of the reported cases making a good recovery [10, 12]. In the largest case series, more than 50% of patients completely recovered in 2 days, and all had Modified Rankin Scale score of 0 after 6 months [15]. In contrast, large territory strokes involving a large volume of the MCA and including the insula understandably have a worse prognosis than stroke involving only the insula [8]. Injury in the insular region may be associated with a poor outcome through several mechanisms, ranging from dysautonomia to cardiac complications and infections [47, 49]. In the studied literature, right hemisphere IS involving the insula had a poorer prognosis and were larger when compared to left hemisphere stroke possibly because of a lack in recognition of mild right insular strokes [50].