Poststroke Recrudescence:
Current Evidence and Considerations for Clinical Practice

Poststroke recrudescence (PSR) is the transient reemergence or worsening of previous stroke-related deficits^1,2 occurring in the context of a stressor after an initial recovery from an index stroke. PSR is not uncommon and may be the final diagnosis in as many as 10% of presentations that are initially concerning for stroke or transient ischemic attack (TIA).^1,2 Despite the high prevalence of this syndrome and the clinical importance of correctly identifying recurrent cerebral ischemia versus stroke mimics, PSR remains poorly understood. A handful of retrospective cohort and clinical case studies^1–6 describing the triggers, clinical features, and risk factors for PSR have been published. We briefly summarize the PSR literature, including the aforementioned studies, and highlight considerations for clinical practice.

Pathophysiology

PSR most commonly is encountered in the setting of toxic metabolic imbalance, systemic infection, or sedative or anesthetic medication use.^1–4 Specifically, PSR is often related to immune response during the index stroke. Preliminary results of a rodent study conducted by Zierath and colleagues⁷ suggest that a cytokine or immune response affecting the brain may contribute to the emergence of PSR in the context of systemic infection. This is attributable in part to increased cytokine release during an index stroke which creates nonspecific brain self-antigens. Consequently, an infection occurring years after the index stroke may result in reemergence of these self-antigens, leading to PSR.⁸

In another study, Becker and colleagues⁹ demonstrated that individuals with acute stroke who developed pneumonia during their initial admission developed primed leukocytes that produced a proinflammatory immune response when exposed to myelin basic protein in culture. Priming to myelin basic protein, in particular, was hypothesized to be responsible for the largely subcortical white matter tract symptoms observed during PSR episodes in that study.

In addition, PSR occurs more frequently after larger strokes, potentially because of higher levels of anti-inflammatory cytokines (namely, interleukin-10), which are associated with a relatively immunosuppressed state and higher predisposition to infection during the acute phase compared with smaller strokes.⁸ As such, it is conceivable that a future infection can result in PSR by means of cytokine-mediated or other pathways.² A greater sensitivity to GABA-inhibitory mechanisms (eg, GABA agonist administration) also has been identified as a possible factor in the reemergence of previous motor and language deficits in patients with a stroke history.^10–13

Evaluation and Diagnosis

Despite recent advances in the understanding of physiologic mechanisms that may underlie PSR, the syndrome is difficult to characterize because of the marked heterogeneity in its clinical presentation. First, characteristics of PSR presentations are varied by nature, because of the heterogeneity in index stroke presentation; however, neurologic deficits in PSR typically are milder compared with those of the index stroke. Second, PSR can occur after both ischemic and hemorrhagic strokes.² Third, Multiple triggers for PSR have been identified, including systemic infection, hypotension, metabolic imbalance, insomnia, stress, and benzodiazepine use.^2,3 In the authors’ experience, PSR also can be induced by a new brain injury, which can result in a mixed pattern of deficits localizing to the index stroke as well as to new areas of ischemia or hemorrhage. Lastly, PSR can be difficult to recognize and diagnose because of a lack of specific serologic or neuroimaging indicators, the transient nature of the associated symptoms, occurrence in individuals with preexisting vascular risk factors, and the lack of studies directly comparing PSR with other causes of transient neurologic symptoms (eg, TIA).

Despite the challenges in recognizing and diagnosing PSR, preliminary diagnostic criteria for PSR have been proposed and documented in the stroke literature. A study by Topcuoglu et al² provides a 5-point model for evaluating and diagnosing PSR (Box). These criteria provide a useful starting point for establishing diagnostic criteria for PSR and guiding clinical practice. However, to our knowledge, these criteria have not been replicated in alternative samples or refined further by appropriate working groups or subject matter experts. As such, further research is needed to validate this framework as a standard of clinical practice.

Management and Prognosis

Appropriate diagnosis of PSR is critical to avoid unnecessary evaluation for recurrent stroke and potentially harmful escalation of stroke prevention medical therapy. Previous reports document that intravenous thrombolysis is well-tolerated in the PSR population.^14,15 As such, PSR considerations should not cause physicians to withold treatment in acute cases where there is diagnostic uncertainty and the patient is otherwise a candidate for intravenous thrombolysis. Following timely diagnosis of the syndrome, identification and management of the precipitating triggers (eg, metabolic correction, sleep restoration, hypertension treatment) is the next objective of PSR treatment and typically results in symptom resolution shortly thereafter.

There is a gap in the literature regarding both short-term and long-term prognosis after PSR. By definition, patients with PSR return to their pre-presentation baseline, generally within hours to days, although approximately 7% of patients may experience recurrence.² In the authors’ collective experience, patients with PSR rarely return with recurrent episodes, which suggests against the likelihood of chronicity and may indicate optimized management of the underlying trigger. However, patients with a history of multiple strokes may be at risk of multiple discrete episodes of PSR, each associated with a distinct index stroke.

The long-term implications of PSR are unknown, and additional aggregated longitudinal data will be necessary to characterize PSR prognosis. Future research also may be geared toward investigating the association between history of PSR and risk of recurrent stroke, poststroke cognitive impairment, or vascular dementia.

Conclusion

As a clinical phenomenon, PSR is not uncommon, but it remains underrecognized. Previous retrospective cohort studies and clinical case reports have broadened our understanding of PSR, including risk factors, triggers, and phenotypes. Given the limited published research on PSR, these cohort and case studies are a critical starting point for recognizing the symptom presentation and understanding the underlying mechanisms of PSR. Given the heterogeneity of inciting stressors and symptoms associated with PSR, a larger body of case data is needed to clarify the natural history and long-term implications of this syndrome.