1.               Introduction

Recrudescence has been characterized variously as a “differential awakening” (cucchiara), a “reexpression of an old stroke” (selmin), and a “reemergence” (lazar) in the literature, contributing to a lack of consistency in the medical terminology employed to describe this not uncommon occurrence^[1-3]. Given the significance of this issue, it is imperative to review the current literature to establish a comprehensive framework for this entity, with the ultimate goal of curtailing unnecessary medical investigations and enhancing diagnostic precision.

Stroke recrudescence, characterized by the reappearance of previously resolved focal stroke deficits following an acute stressor, without detectable acute lesions on mri, remains a relatively unexplored phenomenon within the vascular neurology subspecialty^[4,5]. Frequently mistaken for acute strokes, stroke recrudescence often leads to unnecessary and costly imaging and changes in medication recommendations. Existing literature suggests that recrudescence affects approximately 1 in 10 patients displaying symptoms of a second stroke like event, underscoring the need for in-depth education that elucidates this presentation. This education pursuit can elevate awareness regarding this commonly encountered occurrence and subsequently minimize length of stay, conserve cost, and enhance patient care^[5].

Our objective is to delve into the clinical attributes, common triggers, and potential interventions related to stroke recrudescence. By offering clinical insights and a comprehensive review of the cited literature, we seek to empower clinicians in accurately diagnosing, and effectively managing, instances of stroke recrudescence.

 2.               Case presentation 
A 78 year-old woman presents to the emergency room with 12 hours of worsening right-sided acute on chronic weakness and worsening speech deficits described as word find difficulty, and associated urinary frequency and dysuria. Medical history includes history of left mca ischemic infarct presenting with right side facial droop and right side arm weakness, treated with tpa, paroxysmal atrial fibrillation untreated, hypertension treated with lisinopril and controlled type 2 diabetes managed with sliding scale insulin.

Physical exam findings showed a lethargic and axox3 woman with noticeable focal neurological deficits. Neurological examination showed a right sided facial droop, mild dysarthria, 3/5 strength, with decreased sensation in right upper extremity to pin compared to 5/5 strength and intact sensation of the left upper extremity. Noncontrast ct revealed a chronic infarct territory localized to the left frontal and temporal lobes, but with no evidence of acute ischemia or hemorrhage. Urine analysis showed positive nitrates and positive leukocyte esterase, with urine culture growing gram negative rods suggestive of e.coli. The patient’s neurological deficits dramatically improved after treatment of the urinary tract infection via antibiotic regimen of trimethoprim-sulfamethoxazole.

3.               Discussion

3.1 identifying triggers and provoking factors

Recrudescence manifests with symptoms that closely resemble that of the patient's initial stroke symptomatology, albeit typically with less severity. This characteristic sets it apart from novel strokes, which infrequently impact the identical previously affected brain region. Consequently, this underscores the significance of conducting a meticulous review of patients’ medical records to accurately discern instances of recrudescence.

A plethora of potential triggers can precipitate recrudescence, illustrated in (table 1). An enlightening study by jun-o-connell et al. Revealed that infections (26.5%), metabolic factors (20.6%), hemodynamic fluctuations (5.9%), psychosocial stressors or other triggers (8.8%), as well as the presence of multiple stressors (38.2%) were the most prevalent categories precipitating recrudescence^[5]. In line with these findings, a retrospective analysis identified hypotension, hyponatremia, fever, insomnia, and stress as factors correlated with the onset of recrudescence^[6].

The diverse array of triggers contributing to recrudescence accentuates the necessity for a standardized diagnostic approach aimed at evaluating both the occurrence of recrudescence and its underlying triggers. Such an approach might encompass a comprehensive patient history, toxic metabolic panels, complete blood counts, and monitoring of vital signs.

3.2 provoking factors

Specific retrospective and prospective studies highlighting provoking factors for recrudescence include but are not limited to the following:

3.3 cns depressants and recrudescence

Numerous significant factors have been identified as potential triggers for recrudescence, among them of which includes the use of central nervous system (cns) depressants. Multiple research studies have established a connection between recrudescence and the consumption of controlled substances. The first notable observation of this relationship dates back to 2002, when an article reported the reappearance of stroke symptoms in a patient subsequent to the administration of benzodiazepines^[3]. Since this citation, subsequent investigations have documented cns depressants inclusive of anesthetic agents, benzodiazepines, and opioids as culprits for inciting recrudescence^[6,4].

A limited number of retrospective studies have indicated a correlation between opioid use following an initial stroke incident and the likelihood of recrudescence. For instance, a case report featured a 44-year-old right-handed woman who, after experiencing a right hemispheric stroke, suffered from a week of intense unyielding pain rated in severity as a 9/10. Her diagnosis encompassed vaso-occlusive pain crisis due to a history of sickle cell anemia leading to the administration of a cns depressant. Remarkably, within a few hours she exhibited acute severe focal neurological deficits that mirrored the presentation of her prior known stroke, occurring three years prior. In this case, the trigger for symptomatology and clinical worsening was attributed to intravenous hydromorphone administration^[7]. Another case report narrated the story of a 67-year-old man initially presenting with subarachnoid hemorrhage and subsequently experiencing symptoms akin to a lacunar stroke after undergoing a ct angiogram. Even though the patient and family denied any previous stroke-related symptoms, dedicated neuroimaging revealed evidence of a pre-existing chronic lacunar infarct. In this context, the administration of benzodiazepines and opioids during the ct angiogram was considered a likely trigger for recrudescence^[6].

Some prospective studies have undertaken the exploration of the cns depressant theory as a trigger for recrudescence by conducting midazolam challenges. In one study, a total of 8 patients, 5 with left-sided symptoms and 3 with right-sided symptoms, who had experienced strokes ranging from 7 days to 6 years prior, displayed similar symptoms to their initial strokes when subjected to midazolam challenge. Intravenous midazolam was administered until mild drowsiness was observed. Patients were evaluated during the period of sedation and again after a 2-hour interval when the sedative effects had worn off. The results indicated that among the patients with left hemispheric strokes, 5 demonstrated a recurrence or exacerbation of their initial right hemiparesis and aphasia, but no signs of left neglect. Conversely, the 3 patients with right cerebral strokes displayed the reappearance of left hemiparesis and left visual field neglect, with no aphasia. Importantly, all patients returned to their baseline conditions after a two hour interval clinical assessment^[3].

Differentiation between post-stroke recrudescence vs. Stroke vs. Other stroke-mimicking etiologiesThe necessity for a coherent and uniform definition and set of criteria for recrudescence is underscored by the need to categorize cases that might potentially align with this definition but cannot be definitively categorized as such. In an already broad list of differentials for neurological deficits, recrudescence is set apart, yet similar to other common emergent insults such as stroke or seizures (table 2). Instances of this ambiguity have been identified within retrospective cases. For instance, one case presented with stroke-mimicking symptoms: a 70-year-old woman exhibited right-eye abduction deficit, facial muscle control issues, and difficulty closing the eyes two weeks subsequent to the onset of painful red fluid-filled rashes. Initially diagnosed with shingles and diabetic cranial neuropathy, four years later she displayed left-sided facial paralysis, an inability to raise her left eyebrow, weakened left eye blink, and an ataxic gait alongside vesicular eruptions and crusting erupting on the left side of her neck.

These manifestations were consistent with ramsay hunt syndrome involving the c2 and c3 dermatomes. A subsequent incident revealed no acute infarction on imaging but with chronic pontine infarction and periventricular ischemic changes, which may have accounted for the clinical findings four years prior^[8]. This case exemplifies a combination of components suggestive of recrudescence while also featuring elements that diverge from the phenomenon. In another case, a 59-year-old woman exhibited mild covid-19 symptoms with non-specific neurological complaints such as loss of olfaction, diminished taste sensation, and fatigue, but began having a degree of memory impairment without a neurological exam captured. Two months later she presented with worsening cognitive impairment as well as sensory deficits and novel right sided weakness. Chronic ischemic stroke in the setting of recent covid-19 infection manifesting as memory impairment and acute neurological deficits two months later may be related to stroke recrudescence during the recovery phase of the infection. Due to the ambiguity presented in the cases aforementioned, this underscores the imperative for widespread awareness within the medical community regarding the spectrum of the recrudescence phenomenon and its varied presentations. This will foster a comprehensive understanding and proper protocols, such as conducting and reviewing comprehensive neurological histories and performing complete neurological examinations.

3.4 evaluating traditional medication and imaging

For individuals not well-versed in the concept of recrudescence, these occurrences might bear resemblance to novel acute strokes, even in cases where preventive stroke medications are being taken with compliance. Unfortunately, this resemblance can unwittingly prompt the initiation of unwarranted supplementary antiplatelet or anticoagulant treatment, aligning with prevailing aha/asa stroke guidelines. While intended to mitigate risk, this response may inadvertently heighten the potential for bleeding and other adverse outcomes in a patient without added benefit^[9]. A systematic review underscored that six patients presented (4%), who were ultimately diagnosed with recrudescence, were subjected to unnecessary administration of tissue plasminogen activator (tpa), a relevant potential consequence of misdiagnosis and pursuing inappropriate treatment pathways^[10].

Noting improvement of stroke-like symptoms with removal of triggers, it is important to consider how improving the traditional workup of stroke would be beneficial for both patients and providers. One thing to consider as it pertains to completing a stroke workup is the indication for obtaining vessel imaging such as a cta series. In the cited literature, imaging studies conducted on patients with post stroke recrudescence, in majority of cases, revealed no new acute infarct or hemorrhages, whereas a new stroke with new neurological deficits would show infarct or hemorrhage in a different area of the brain^[10]. Although a ct and/or cta study series is relatively quick and easy to obtain in emergent situations, this leads to an extended window for the patient’s potential improvement. This may also result in an augmentation of hospital expenses and over-allocation of resources. It is vital to have someone on the emergency team reviewing history of prior stroke(s) and comparing these findings to the presenting signs and symptoms of the current episode declared. If novel signs and symptoms are apparent, then continuing with the standardized stroke protocol is appropriate. If the same symptomatology is discerned, then recrudescence ought to be considered with workup focused on potential provoking factors; this can expeditiously narrow the differential of potential etiologies, and targeted treatment be applied more promptly.

Table 2. Differential diagnosis and characteristics for recrudescence and recrudescence mimics

1.               Conclusion

In conclusion, the phenomenon of recrudescence, characterized by the reemergence of previously resolved stroke-like symptoms following acute stressors, presents a challenging and relatively unexplored area within the realm of vascular neurology. It is important to be aware of the various aspects of this phenomenon, shedding light on its clinical attributes, common triggers, and potential interventions. The comprehensive review of literature underscores the importance of a standardized diagnostic approach, emphasizing the need to differentiate recrudescence from other stroke-related conditions and stroke-mimicking etiologies.

Triggers for recrudescence encompass a wide spectrum of factors, ranging from infections and metabolic dysfunction to autonomic disturbances and psychosocial stressors. Notably, cns depressants, such as benzodiazepines and opioids, have emerged as significant contributors to the occurrence of recrudescence, prompting the need for heightened vigilance when administering such medications to stroke survivors.

Misdiagnosis of recrudescence as a new stroke can lead to inappropriate treatment interventions, emphasizing the necessity for accurate differential diagnosis. This paper highlights the potential benefits of refining traditional stroke workup methods, including the judicious use of imaging, such as ct angiography, to discern between recrudescence and acute strokes.

By aggregating and summarizing existing research, this paper contributes to a better understanding of recrudescence and its diverse manifestations. Awareness among healthcare providers of this phenomenon's intricacies and triggers can lead to improved patient care, timely interventions, and informed treatment decisions. Ultimately, a deeper comprehension of recrudescence can enhance diagnostic accuracy, streamline medical investigations, and elevate the quality of care provided to individuals experiencing this recurrent neurological occurrence.

2.               Data availability

All data reviewed and discussed was found in scientific papers which were cited in the references section.

3.               Conflict of interest

All authors affirm there are no conflicts of interest with research endeavors.

4.               Funding statement

This work did not receive any funding.

References

1.    Cucchiara rf. Differential awakening. Anesth analg 1992;75(3):467.

2.    Magdy sh, torbey mt. The stroke book. Cambridge university press 2013.

3.    Lazar rm, fitzsimmons bf, marshall rs, et al. Reemergence of stroke deficits with midazolam challenge. Stroke 2022;33(1):283-285.

4.    Eva ra, topcuoglu ma, singhal ab. Post-stroke recrudescence from infection: an immunologic mechanism? Translational stroke research 2018;10(2):146-49.

5.    Jun-o’connell ah, henninger n, moonis m, silver b, ionete c, goddeau rp. Recrudescence of old stroke deficits among transient neurological attacks. The neurohospitalist 2019;9(4):183-189.

6.    Falatko sr, schmalz pgr, harrigan m. Recrudescence of symptoms of remote ischemic stroke after a cerebral angiogram. World neurosurg 2017;101:814.

7.    Bernstock jd, budinich cs, cohen lg, awosika oo. Recrudescence of focal stroke symptoms during pain management with hydromorphone. Frontiers in neurology 2016;7.

8.    Coban e. A stroke mimic: post-stroke recrudescence syndrome triggered by ramsay hunt syndrome. Tur j neurol 2021;27(3):318-321.

9.    Correction to: 2021 guideline for the prevention of stroke in patients with stroke and transient ischemic attack: a guideline from the american heart association/american stroke association. Stroke 2021;52(7):483-484.

10. Topcuoglu ma, saka e, silverman sb, schwamm lh, singhal ab. Recrudescence of deficits after stroke. Jama neurology 201;74(9):1048.