Monitoring nightmares, hallucinations ‘extremely valuable’ in lupus, early flare treatment
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Nightmares and hallucinations may occur at any stage of disease course in patients with systemic lupus erythematosus, according to recent findings.
The data, published in The Lancet’s eClinicalMedicine, additionally suggest that a “range” of neuropsychiatric symptoms may a harbinger of SLE onset and flares. As such, the researchers stressed that clinicians should consider asking patients about these symptoms, as they can be more common than their current focus among physicians suggests.
“For many years, I have heard patients with SLE mentioning nightmares as a possible symptom of their disease flaring,” David D’Cruz, MD, FRCP, a consultant rheumatologist at the Louise Coote Lupus Unit at Guy’s and St. Thomas’ Hospitals, in London, told Healio. “This was often in the context of other neuropsychiatric symptoms such as hallucinations, hearing voices or seeing things that were not visible to others.
“I thought that this was worth investigating as a possible warning sign of a disease flare,” he added. “This collaborative research has confirmed my clinical observations and has important implications for clinical practice.”
D’Cruz and Melanie Sloan, PhD, of the department of public health and primary care unit at the University of Cambridge, in the United Kingdom, and colleagues, investigated 29 neuropsychiatric symptoms in relation to the timing of SLE onset. They also investigated whether neuropsychiatric symptoms could be a harbinger of other autoimmune diseases or flares of existing conditions.
The analysis included survey data from 675 patients with SLE and 400 clinicians, along with interview data from 69 patients with various autoimmune conditions and 50 additional clinicians.
According to the researchers, the majority of neuropsychiatric symptoms did not present around the time of SLE onset, as was previously thought. Among patients who reported hallucinations, 54% reported the first experience with this phenomenon more than a year after SLE onset.
In addition, findings from the interview portion of the study showed that a “range” of neuropsychiatric symptoms may be a prodrome to onset of SLE or other conditions and flares. Other data demonstrated that disruption of dreams preceded hallucinations among patients experiencing this prodromal syndrome.
Healio sat down with D’Cruz and Sloan to discuss why neuropsychiatric symptoms may occur at any point during SLE or autoimmune disease course, why rheumatologists should have these symptoms on their radar, and where research into these phenomena needs to go next.
Healio: Why did you decide to study these particular neuropsychiatric symptoms in SLE?
Sloan: Our research ethos is that we start with the patients and what they want us to research, and what they are actually experiencing. The current neuropsychiatric symptom criteria used by many rheumatologists is the American College of Rheumatology criteria, and that was designed by physicians in the last century. Although it has played an important role, most clinicians in our study felt that it was limited and outdated. We are now in a more modern era where patient views and experiences are — or certainly should be — given much more weight in designing studies and, hopefully, in designing criteria.
So, instead of only collecting data on the limited range of symptoms that physicians in the last century decided may be a part of their disease, we started by asking the patients on online forums, and in disease support groups, “What symptoms are you experiencing?”
As we discovered, due to high levels of under-eliciting and under-reporting of these types of symptoms, clinicians often are not aware of the type and frequency of neuropsychiatric symptoms, so it is vitally important that we fully involve patients in research.
Healio: In what other autoimmune disease patient populations are such neuropsychiatric symptoms common?
D’Cruz: These symptoms are most commonly associated with SLE, but I have occasionally seen them in patients with Sjögren’s syndrome.
Sloan: A disease that is very neglected in research, and that patients feel is also often neglected in care, is undifferentiated connective tissue disease (UCTD). Our patients with UCTD had similar types and frequencies of neuropsychiatric symptoms to our lupus patients. Yet they often reported that they felt their symptoms were dismissed, disbelieved or not considered by clinicians because they often did not have the typical biomarkers or objective test results to validate their reports.
Several clinicians in the study said UCTD and Sjögrens disease were considered mild and do not usually have organ involvement. Yet to patients, these diseases rarely felt mild and the brain/nervous system symptoms they frequently reported should potentially have more consideration as being organ involvement in some cases. The brain, after all, is an organ.
Healio: What are the possible mechanisms at work in these symptoms?
Sloan: With increasing awareness of the effects of peripheral inflammation on the brain, it seems plausible that many diseases will have neuropsychiatric symptoms directly caused by their disease. It is important to also consider the life-changing nature of these diseases, which increases mental health symptoms like depression and anxiety by the indirect effect, as well as the impact of medications such as corticosteroids, which can of course cause neuropsychiatric symptoms.
Healio: Why did you think these symptoms could be associated with SLE onset or flares?
Sloan: We have found in our previous work with patients that they often are very aware of which symptoms are a bad sign — a sign that their disease is about to worsen. This varies a lot between patients, but often followed a similar pattern in each flare for each patient. For example, one patient described a “tingling feeling all over” before her psychotic experiences, and another described feeling “over excited,” a “sense of unreality” and nightmares before her flare ups.
Many of these terms are patient descriptions and not currently considered to be a part of these diseases, so they are rarely elicited or discussed with clinicians. It really highlights the importance of time spent with each patient eliciting their views and experiences of their own symptoms. Symptoms might not fit into neat boxes or existing diagnostic criteria, but they might be extremely valuable in monitoring that patient’s disease and treating flares at an earlier stage.
Healio: It seems hallucinations did not appear around SLE onset, as was previously thought, with 54% reporting first presentation more than 1 year after disease onset. What are your thoughts on this finding?
D’Cruz: This is a useful point when trying to distinguish patients who have a mental health diagnosis, such as a psychosis, that is a separate diagnosis from SLE, as this will usually have presented before the disease if it was a primary psychiatric disease. We have also seen patients with neuropsychiatric symptoms related to SLE at the time of diagnosis or developing later in the disease course.
Sloan: Many rheumatologists said it was an established theory that these types of symptoms would usually occur around the time of diagnosis. Our study found two major problems with this. One is that the time of diagnosis is rarely the same as the time of symptom onset due to long diagnostic delays. The other is that many clinicians were passing this established theory down to their juniors, yet during interviews they acknowledged that they did not have a medical rationale for this theory.
It then means that clinicians are less likely to expect later onset neuropsychiatric symptoms. Consequently, they may be even less likely to ask about and normalize these symptoms. Our findings suggest that these symptoms can first occur before diagnosis — possibly as a prodrome to the disease, or as one of the first disease symptoms that is not recognized until after the more common symptoms occur — as well as around the time of diagnosis and at varying stages after diagnosis, including many years later.
Healio: You described “a range” of neuropsychiatric symptoms. What are some of the most common?
Sloan: One of the most common neuropsychiatric symptoms was cognitive dysfunction. This could range from severe confusion to mild memory or attention difficulties. Mood changes were also common. Depression is commonly associated with these diseases, both as a direct effect of inflammation on the brain and as an understandable human reaction to an unpleasant and often life-changing disease.
High mood was also reported by some patients at the start of a disease flare, described as a euphoric, manic, “drunk” or “over-excited” feeling. This was felt by clinicians, particularly neurologists, to be much more likely to be directly attributable to the disease itself. It is also often more detectable, as it can be more visible in behaviors than depression or low mood, which some patients said they tried successfully to disguise from their clinicians.
Healio: How about the most serious or severe symptoms? Were they nightmares, hallucinations or something else?
D’Cruz: Patients report that nightmares are frequently frightening — for example, images of accidents, or people trying to kill or harm them or their families. We used the term daymares to describe these symptoms occurring during the day, and it is a useful way of asking patients about auditory, visual or tactile hallucinations and other neuropsychiatric symptoms.
Sloan: What is considered most serious or severe differs greatly between clinicians and patients. Patients tell us that their clinicians can be understandably focused on life- and organ-threatening symptoms, yet the persistent non-life-threatening symptoms mean that many patients report that they have no quality of life.
Although clinicians often thought that hallucinations, mania and seizures would be the most serious to patients, patients actually find the fatigue and cognitive dysfunction much more changing. This was partly due to these symptoms being much more frequent and less treatable — or treated — than those considered more severe to clinicians.
A patient may experience distressing nightmares and hallucinations in a major disease flare, but these would usually be of shorter duration than the often ongoing fatigue. Fatigue is consistently the symptom that patients say is ruining their lives, making them unable to do more than just exist at times, rather than enjoy a normal life.
Cognitive dysfunction often also has a huge impact on patient’s lives, particularly their ability to study, work and socialize. We found many patients had lost their confidence and so were sometimes withdrawing from everyday life for fear of embarrassment if they had memory lapses or forgot words when speaking.
Healio: Is there any indication of why some patients experience these symptoms early in the disease course and others experience them later?
D’Cruz: The reasons for this are not understood.
Healio: What do the patterns of these symptoms tell us about disease course and progression in SLE or other autoimmune conditions?
D’Cruz: The development of neuropsychiatric symptoms in a patient with SLE can be an indicator of other organ involvement, especially renal disease. The problem is that patients frequently do not volunteer these symptoms due to embarrassment or fear that they may be admitted to a psychiatric unit.
Healio: How can your findings inform treatment paradigms for SLE and other conditions where patients are experiencing these symptoms?
Sloan: The problem remains largely one of attribution. It is unclear whether the symptoms in an individual are due to the direct disease effect, or to the indirect effect of having a difficult disease, or to medications, or are completely unconnected to the disease. If the same symptoms appear consistently in each flare, come at the same time as other non-neuropsychiatric symptoms such as rashes or kidney involvement, and respond to immunosuppression, then there is greater evidence that the symptoms are directly related to the disease.
Although we believe that many of these symptoms may respond well to immunosuppression in some patients, all patients with chronic diseases also need much more support in adapting to living with their diseases. We need to work towards optimum medication and non-medication support tailored to each individual.
Healio: What message can rheumatologists take from your findings into their daily practice?
D’Cruz: The main point of this important research is that clinicians should consider asking patients sensitively about these symptoms, as they are common. Another important and unexpected finding was the prevalence of suicidal ideation.
Sloan: Ideally, clinicians will work with each of their patients to ascertain, document and monitor that individual’s own usual progression of symptoms in a flare. This may lead to the identification of early warning symptoms that could lead to earlier treatment. Listening to patients and their view on the attribution and progression of their symptoms not only may help with identification, attribution and treatment plans, but also build up trust.
References:
Sloan M, et al. eClin Med. 2024;doi:10.1016/j.eclinm.2024.102634.
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