CONTENTS:
Cognitive Impairment in ITP
The quality of life of many ITP patients is reduced due to the daily burden of living with this rare autoimmune bleeding disorder and the poorly understood biologic effect of ITP. Most clinicians now recognize that ITP negatively impacts a person’s overall mental health and physical health, increasing fatigue and reducing overall energy levels. However, what is less discussed is how the disease impacts cognition. Emerging data suggests some ITP patients suffer from cognitive impairment, affecting their ability to understand and perform certain tasks.
Cindy Neunert, MD, MSCS, from Columbia University Irving Medical Center, in New York, NY, presented on cognitive impairments seen in individuals with ITP. Her objectives included describing cerebral bleeding events associated with ITP, reviewing data on cognitive impairment, and exploring potential relationships between cognitive decline and other disease manifestations.
Cerebral bleeding events in ITP
Intracranial bleeding (bleeding in the brain) severe enough to impair sensation or motor activity is a rare complication of ITP. The incidence of intracranial bleeding is estimated to be less than 5% in adult ITP populations over a lifetime and even less in pediatric patients. While there are no universal predictors of risk, there is data in one study to suggest the risk is higher in those who have already had serious bleeding events that required rescue therapy, such as hematuria (obvious blood in urine). There is no single platelet threshold that on its own leads to threatening bleeding or intracranial bleeding, but current guidelines suggest a platelet level less than 20,000-30,000/µL, especially less than 10,000 in adults, may increase bleeding risk.
Most research to date has focused on obvious, visible bleeding events that result in notable clinical symptoms. More recently, however, investigators have looked at whether patients have small bleeds, called cerebral microbleeds (CMBs), that physicians may not detect clinically. One such place where these small bleeds can occur is in the brain, In the general population, microbleeding in the brain occurs in as many as 6.5% of adults between the ages of 45-50, and 17% between ages 60-69, and can be associated with vascular events and dementia (cognitive decline).
In a recent study that enrolled ITP patients who had a platelet count less than 30,000 at some point, it was reported that 43% of participants had microbleeds. When patients were further categorized based on their lowest ever platelet count, 60% of those with a count less than 5,000 had microbleeds. Among those who had a lowest platelet count between 5,000-9,000, 36% had microbleeds. This value fell to 22% in participants who had a lowest platelet count between 10,000-14,000. No age-matched participants in the study’s healthy control group showed microbleeds. This data suggests that microbleeds are more common the lower the platelet count is. CMBs were also more commonly seen in adults with chronic ITP, suggesting they accumulate over time if a very low platelet count persists. Most adults who had microbleeds also had higher organ bleeding scores. Unlike in the healthy control group where younger age was protective against CMBs, this study found that age was not associated with the number of CMBs in ITP participants. Unlike some previous studies, there were no CMBs detected in the healthy control group, which was comprised of young adults without ITP. CMBs have also been similarly seen in children with ITP with marked thrombocytopenia. This research was presented by Dr. Alice Hart, a Clinical Research Fellow in non-malignant haematology and paediatric haematology at Imperial College and Imperial College Healthcare NHS Trust in London, UK.
Cognitive impairment in ITP
Dr. Neunert shared results from another research study. Sixty-eight adults with ITP who had a platelet count under 30,000 were surveyed using a standardized tool for assessing cognitive decline, called CANTAB (Cambridge Neuropsychological Test Automated Battery). Responses from the survey were used to look at:
- (a) long-term memory of a specific event that was personally experienced at a particular time (episodic memory)
- (b) Participants’ ability to plan, focus, and remember instructions and juggle tasks (executive functioning)
- (c) how quickly they could understand information and respond to it (processing speed)
- (d) short term memory capacity (working memory)
- (e) ability to focus and concentrate on a task (attention)
Within these cognitive domains, participants were categorized as being impaired or not impaired. Fifty percent of participants had cognitive impairment in at least one of the five cognitive domains, notably episodic memory (22%) and executive functioning (19%). When bleeding scores were included in the analysis, participants who had a higher bleeding score had more deficits in episodic memory. However, this study interestingly reported that CMBs were not associated with cognitive impairment.
David Kuter, MD, one of PDSA’s medical advisors, and his research team reported similar findings in their study, but with some differences. This study looked at adults with ITP enrolled in the clinical trial for a drug called rilzabrutinib, an oral BTK inhibitor. Participants were also assessed for neurological impairment in four domains of cognitive function:
- (a) psychomotor function (physical movement)
- (b) attention
- (c) learning ability
- (d) working memory
The study found that there was moderate impairment in attention and psychomotor function and mild impairment in memory.
Comments from PDSA Medical Advisors:
These are provocative but very early findings. Unfortunately, the two sets of findings were not consistent as to the effects of microbleeds and exactly which type of cognitive impairment predominated. The clinical significance of microbleeds is not established and requires longer-term follow up to see if the number of microbleeds continue to increase and if neurological findings appear over time; or if microbleeds portend more serious bleeding. There are many reasons besides microbleeds why patients with a chronic serious disorder might score low on one or another test of cognition, including effects of medication, anxiety, fatigue, sleep disorders, and unclear biologic effects. Many of our patients, despite clinically problematic ITP, maintain or resume active lives and careers that require a high level of cognitive function. The importance of the studies is suggestive. If a relationship between otherwise inapparent microbleeds (or any other clinical or biologic findings) and cognitive function is established, or if microbleeds predict more serious bleeding, it may impact surveillance and alter (increase) what are considered acceptable thresholds for platelets in selected individuals.
