“For many years, I have heard lupus patients mention nightmares as part of their lupus flares, especially if they have neuropsychiatric lupus,” says David D’Cruz, MD, a world-renowned lupus specialist at Guy’s and St. Thomas National Health Service (NHS) Foundation Trust in London. The mixed methods Investigating Neuropsychiatric Symptom Prevalence and Impact in Rheumatology patient Experiences (INSPIRE) study has confirmed the observation.1
Dr. D’Cruz believes the results reinforce the idea that listening carefully to patients and taking their symptoms seriously strengthen patient trust in the clinical team. Unfortunately, he says, neuropsychiatric lupus can be difficult to diagnose, largely because most rheumatologists don’t often ask about psychotic symptoms.
The interviews captured in the study revealed that not only were the patient-reported prevalences of neuropsychiatric symptoms significantly higher than those estimated by most clinicians, but the patient data conflicted with research reporting nervous system involvement as being unusual in rheumatoid arthritis, rare in Sjögren’s disease and rare in systemic sclerosis.
Most research designed in the last century did not center on patient experience, Dr. Sloan explains. She and her colleagues concluded in their paper that a self-perpetuating cycle in rheumatology may exist in which neuropsychiatric symptoms are under-elicited in the clinic, under-identified in research and excluded from clinical trial outcomes, and consequently, they are rarely—or not—included in SARD criteria/guidelines. The new data are, thus, a step forward in remedying that situation, and the authors call for improved inter-specialty communication and greater patient involvement in SARD care and research.
Dr. Sloan and her co-authors expressed optimism that this change will happen because most of the clinicians interviewed for the study were highly motivated to improve SARD neuropsychiatric care.
Clinical Experience
Dr. D’Cruz has spent approximately 30 years seeing patients with lupus. “The patients are not just reporting dreams,” he says. “They frequently report severe nightmares that are terrifying.”
These nightmares include people trying to kill them or life-threatening events directed at the patient or family. They can also include alarming experiences, such as relatives dying in car or airplane accidents or large objects hurtling toward the dreamer. Taken together, repeated nightmares can be classified as nightmare disorder.
Although Dr. D’Cruz acknowledges that neuropsychiatric lupus “is still a big black box in rheumatology,” he considers these nightmares to be the telltale sign of neuropsychiatric lupus. Unfortunately, says Dr. D’Cruz, patients who report nightmares often also have suicidal ideation that they haven’t mentioned to anyone.
Dr. D’Cruz explains that although depressive and anxiety symptoms are commonly experienced as a reaction to increased disease activity, experiencing these symptoms, as well as nightmares, before a flare is potentially more suggestive of the direct impact of an incipient lupus flare on the brain, as opposed to the brain’s reaction to a flare.
Dr. D’Cruz and Dr. Sloan propose that these nightmares and disrupted sleep patterns may indicate heightened cerebral arousal related to the immunological inflammation associated with systemic lupus erythematosus (SLE). The hypothesis is consistent with research suggesting neuropsychiatric lupus is associated with autoantibody, cytokine production within the central nervous system and blood-brain barrier disruption. Consistent with this, Dr. D’Cruz has found nightmares often subside as the lupus flare is treated.
Neuropsychiatric lupus involves cerebral inflammation, says Dr. D’Cruz, but brain scans and cerebrospinal fluid analysis are often normal and, therefore, not diagnostic. Moreover, while an electroencephalogram (EEG) can sometimes be abnormal in patients with neuropsychiatric lupus, an EEG is rarely helpful for diagnosis. Neuropsychiatric lupus must be diagnosed clinically.
A comparison of a patient with schizophrenia to a patient with lupus and neuropsychiatric symptoms, explains Dr. D’Cruz, reveals that patients with lupus and psychosis can differ in several ways. For example, patients with neuropsychiatric lupus who experience hallucinations often have some insight into realizing these symptoms are part of their lupus. Patients with neuropsychiatric lupus may also experience seizures. Neuropsychiatric symptoms can first present at any stage in the SLE disease course. Dr. D’Cruz and his colleagues recommend that, when attributing neuropsychiatric symptoms to lupus, rheumatologists consider the timing of those symptoms relative to the timing of SLE symptom onset.
Greater recognition of prodromal, early neuropsychiatric symptoms could enable quicker flare identification and treatment with immune suppression in combination with an antipsychotic. Dr. Sloan adds that although such symptoms as fatigue and cognitive dysfunction are often considered challenging to treat or multifactorial for many patients, she and her colleagues have heard from many patients treated with belimumab, cyclophosphamide or other medication who felt their fatigue and cognitive dysfunction improved or resolved with treatment. This anecdotal evidence suggests a possible direct relationship between neuropsychiatric symptoms and the disease process in some patients, says Dr. Sloan.
Focusing on Lupus
The research on neuropsychiatric symptoms and SARDs provided the foundation for research focusing on patients with SLE. Dr. D’Cruz explains that Dr. Sloan has a “huge online cohort of lupus patients.” The research team used this cohort of more than 1,800 patients with lupus and other patients with inflammatory autoimmune diseases, as well as Dr. D’Cruz’s clinical observation that nightmares often preceded SLE flares, as a basis for their study, which sought to identify a clinically helpful neuropsychiatric prodrome of SLE.
“The dreaming aspect was actually only one of the many symptoms that we studied,” says Dr. Sloan. “Most of the symptoms were included in the study because patients asked us to, or from us asking patient groups what symptoms they were experiencing. Our team research ethos is that we always start with the patients, what they want us to research, and what symptoms they are actually experiencing.”
The investigators surveyed patients and requested that, as a control, the patients ask a healthy person to fill in the same questionnaire. The researchers also sent questionnaires to rheumatologists, neurologists and psychiatrists. The team then performed exploratory qualitative analyses of 36 neuropsychiatric symptoms in SLE and other SARDS. Many of these neuropsychiatric symptoms had never been explored in rheumatology patients. They proposed two criteria as clinically helpful in identifying prodromal symptoms: 1) within-person similarity of prodrome symptoms in recurrent flares, and 2) degree of similarity of prodromal symptoms among patients.
The researchers found that SLE patients much more commonly experience nightmares and other neuropsychiatric symptoms when compared with a cohort of their socio-demographically matched, physically healthy friends.
“We would encourage patients to keep symptom journals and monitor the changes in symptoms when their disease is active and becoming more active,” says Dr. Sloan. “What we found was that most patients had a similar progression of symptoms in each of their flares, although each person often had a pattern of symptoms and progression unique to them.”
The majority of SLE patients who experienced hallucinations, for example, had increasingly disrupted dreaming sleep preceding their hallucinations. Many patients experienced their first episode of neuropsychiatric symptoms more than one year after the onset of their other SLE symptoms, but neuropsychiatric symptoms could first present at any stage of the disease course of SLE, including the period before a formal validated diagnosis of SLE. Such symptoms as increasing nightmares, sensory disturbances or sudden mood changes, while often not prioritized by clinicians and patients for discussion and monitoring, appeared to be frequent precursors of more tangible disease activity.
Translating the Findings
Dr. D’Cruz and Dr. Sloane initiated their research out of concern that misattribution of early SLE and other SARD neuropsychiatric symptoms might lead to suboptimal or incorrect treatment, as well as persisting psychological damage and patient distrust in clinicians. Their findings reinforced their concerns, but the fact remains that diagnosing neuropsychiatric lupus is challenging, even in expert centers with multidisciplinary teams that include rheumatologists, neurologists, psychiatrists and neuroradiologists.
“What are the criteria you use to diagnose neuropsychiatric lupus?” asks Dr. D’Cruz. “That is where the problem arises. … History is everything.”
In their paper, Dr. D’Cruz and colleagues propose that the best approach to initiating a discussion of neuropsychiatric symptoms is to ask the patient about disrupted sleep and dreams and use more descriptive and less stigmatized language, such as “daymares” rather than “hallucinations.” Such an approach may encourage patients to be open in reporting these often feared and stigmatized symptoms. The bottom line, says Dr. D’Cruz, is to ask and then carefully listen to the answer, searching for emerging patterns and themes within that answer. If patients give even a hint of psychiatric symptoms, especially psychotic symptoms, then clinicians should consider a referral for a psychiatric opinion.
Dr. D’Cruz hopes that the new findings will help destigmatize neuropsychiatric symptoms, and that the consequent discussion of neuropsychiatric symptoms in a safe and nurturing environment will reassure patients. “It’s another spectrum of lupus,” says Dr. D’Cruz. “It’s not easy to diagnose or treat, but it is very treatable.”
Pediatrics
Unfortunately, since neuropsychiatric symptoms are more common in pediatric patients, their disease burden from neuropsychiatric lupus is higher. Moreover, Dr. D’Cruz has found that juvenile patients don’t readily mention psychiatric symptoms to their doctors. “You’ve just got to give the patients time,” he emphasizes, adding that, unfortunately, most rheumatologists are so focused on the complex nature of patients with lupus that they often do not have the time to ask about psychiatric and neurological symptoms.
In some cases, says Dr. D’Cruz, pediatric patients spontaneously mention that they have “pretty scary nightmares.” He often asks those patients if they hear voices, and sometimes, in response, he says, “It all comes tumbling out.”
Absent such an obvious opening, he recommends rheumatologists begin by asking patients about their sleep. If patients mention nightmares, then the next step is to ask if the patient has experienced nightmares while awake (i.e., daymares). This can lead to a discussion of visual, auditory, tactile, or olfactory hallucinations.
Both Dr. D’Cruz and Dr. Sloan believe such specific questioning in the clinic, using non-judgmental and nonthreatening language, may reveal that neuropsychiatric symptoms are far more frequent than previously reported.3 Once revealed, the symptoms can be treated. “These young people can bounce back really quickly,” says Dr. D’Cruz, if they receive the appropriate treatment.
Bottom Line
It’s important for patients to learn about their unique progression of symptoms, explains Dr. Sloan. For example, one patient may experience increased nightmares and tremors and feel spaced out before a flare, and another may feel manic and anxious and experience a loss of balance.
“As with many of these symptoms, increasingly disrupted dreaming sleep seems to be an indication of an impending flare in some patients,” says Dr. Sloan.
If patients can recognize and communicate a pattern to their rheumatologists, preempting or reducing a disease flare-up may be possible. Such conversations can be used to build treatment plans and physician-patient trust, leading to much-improved lives for many patients.
“Lupus really is a multi-system disease,” says Dr. D’Cruz. “Listen to the patient. … Try and put it all together, and make a story out of it. … Neuropsychiatric lupus is not all gloom and doom.”
Lara C. Pullen, PhD, is a medical writer based in the Chicago area.
References
- Sloan M, Bourgeois JA, Leschziner G, et al. Neuropsychiatric prodromes and symptom timings in relation to disease onset and/or flares in SLE: Results from the mixed methods international INSPIRE study. EClinicalMedicine. 2024 Jul;73:102634.
- Sloan M, Wincup C, Harwood R, et al. Prevalence and identification of neuropsychiatric symptoms in systemic autoimmune rheumatic diseases: An international mixed methods study. Rheumatology (Oxford). 2024 May 2; 63(5):1259–1272.
- D’Cruz DP, Sloan M. Clinical observation: Are nightmares a manifestation of neuropsychiatric lupus? Rheumatology (Oxford). 2023 Jun; 62(6):2030–2031.
