Neurological Manifestations of Cryoglobulinemia: A Rare but Overlooked Condition in South Africa

Background: Cryoglobulinemia is a rare immune-mediated condition, in which abnormal proteins (cryoglobulins) precipitate at cold temperatures, leading to blood vessel inflammation. It affects approximately 1 in 100,000 individuals globally and often goes undiagnosed due to its overlapping symptoms with common conditions such as stroke. When the central nervous system (CNS) is involved—primarily in Type 2 cryoglobulinemia—it can cause serious neurological events, including seizures, confusion, and stroke-like episodes. Despite this, there is limited awareness and minimal research on this condition in South Africa. Objective: The aims of this study were to describe neurological manifestations of cryoglobulinemia using global case reports, evaluate outcomes associated with delayed diagnosis, and highlight the importance of early detection in patients with unexplained neurological symptoms. Methods: A qualitative systematic review of published case reports (2015–2024) was conducted. The study focused on adults (≥18 years) who were diagnosed with cryoglobulinemia involving CNS manifestations. Reports from hospital-based studies in Europe, North America, and Asia were retrieved from medical databases. Data on symptoms, diagnosis, treatment, and outcomes were summarized numerically and by identifying common patterns. Results: Seventeen relevant cases were identified. The most common neurological symptoms were ischemic stroke (35%), reversible posterior encephalopathy syndrome (24%), seizures (18%), and intracranial hemorrhage (12%). Most cases were associated with Type 2 cryoglobulinemia. Neuroimaging frequently revealed vasculitis, infarcts, or cerebral edema. All patients received immunosuppressive therapy, mainly corticosteroids. Outcomes showed that 76% improved, 12% partially recovered, and 12% died—mostly due to delayed diagnosis. Conclusions: Neurological involvement in cryoglobulinemia is uncommon but potentially fatal. Stroke-like presentations dominate due to vasculitis injury and vascular occlusion. Early diagnosis significantly improves outcomes, while delays can be deadly. Increased clinical awareness is essential in South Africa, where this condition is rarely reported. Clinicians should consider cryoglobulinemia as a possible cause in patients presenting with unexplained neurological symptoms.