‘Poorly understood’ and rife with mimics: Rheum-neuro diseases require a team approach
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For all the multitudes of diseases and diversity of organ systems rheumatologists are adept at managing and analyzing, the brain, spinal cord and related neurological conditions are often not among them.
And yet, there is no shortage of diagnoses shared between rheumatology and neurology, and understanding the techniques and practices common to the latter specialty is often critical to managing patients with complex autoimmune and nervous system complaints.
Source: Tyler Allison, MD, and Julia Harris, MD.
“The list of diagnoses that can be shared between our two specialties, to the benefit of our patients, is incredibly long,” Tyler Allison, MD, director of the pediatric neurology residency program at Children’s Mercy Kansas City, told Healio Rheumatology.
Central nervous system (CNS) lupus is on that list, along with primary or secondary CNS vasculitis and dermatomyositis. The connection doesn’t end there, however. Understanding the nature of the nervous system is essential for rheumatologists whose patients may be experiencing a variety of symptoms under the rheumatology umbrella, according to Laura C. Cappelli, MD, MHS, MS, assistant professor of medicine in the division of rheumatology at Johns Hopkins University School of Medicine.
“It is definitely difficult for us to tell what is going on sometimes, whether it is nerve pain or joint pain, whether the pain is originating in the central or peripheral nervous system,” she said. “Small fiber neuropathy can affect any part of the body and can cloud the picture.”
In short, because neurological manifestations can crop up in myriad ways, rheumatologists and neurologists “have to work together,” Cappelli said.
As such, neurology professionals are often required to weigh in and manage patients with these rheumatic conditions. That collaboration begins with understanding what each specialist can bring to the table. Rheumatologists are trained to look at the big picture and deal with almost any organ system in the body as needed. Neurologists, on the other hand, are taught to focus on the exact source of a problem in the CNS or peripheral nervous system.
Once the issue has been identified, treatment similarly often requires intervention from both sides, according to Elliot Dimberg, MD, associate dean for academic affairs at the Mayo Clinic Alix School of Medicine, and consultant in the department of neurology at the Mayo Clinic.
“Treatment of neurological manifestations of rheumatological disease is most often targeted toward the management of the underlying rheumatological disorder,” he said.
Treatment paradigms, then, can involve immunomodulation, steroids or an increasing reliance on biologics. Both specialists are required not only to understand how these therapies work, their contraindications and all potential impacts they may have on the body and brain, but to communicate this information to patients.
Audra Horomanski, MD, clinical assistant professor of immunology and rheumatology at Stanford University, explained why this last point is so important.
“For patients, it is always helpful to know why they are taking the medications they are taking,” she said. “Also, it is necessary for patients to know the roles of the providers who are managing their care.”
Regardless of who makes the diagnosis, any patient who requires intervention from both rheumatology and neurology should be handled with the utmost caution. That begins with ongoing and open lines of communication between the two specialists.
Skills ‘Most Rheumatologists Do Not Have’
First and foremost, Cappelli stressed that every patient is different and requires a unique approach based on their presentation, symptoms and underlying demographic information.
“Generally, neurologists have been trained to localize the problem to a particular part of the nervous system,” she said.
This entails a comprehensive physical exam that is different from the type of physical exam performed by a rheumatologist, noted Cappelli.
“Neurologists are also trained in neurodiagnostic techniques that can range from a skin biopsy to imaging analyses of the brain or spinal cord,” she said. “These are skills that most rheumatologists do not have, at least not to the same degree.”
Rheumatologists may also lack familiarity with the basics of imaging analyses used in neurology.
“If you are worried about the peripheral muscles and nerves, then a nerve conduction study is useful,” Cappelli said. “For issues in the CNS, an MRI or EEG may be more useful.”
Meanwhile, rheumatologists can contribute expertise about the immune system, along with an understanding of the skin, lungs, joints, kidneys and other systems.
“We also have more experience with a wider variety of immunosuppressive medications,” she said.
Factor in the type of physical exam performed by a rheumatologist, and Cappelli suggested that the two specialties actually have quite “complementary” skill sets.
However, these complementary skills do not always ensure effective patient management. Knowing what to look for and when to speak up is essential.
“Rheumatologists can ask about paresthesias, significant headaches, cognitive changes and movement concerns,” Julia Harris, MD, pediatric rheumatologist at Children’s Mercy Kansas City, and associate professor of pediatrics at the University of Missouri-Kansas City, told Healio Rheumatology. “Vision changes and psychiatric symptoms are also important to evaluate for, as these complaints could lead to involvement of ophthalmology and psychiatry/psychology, respectively, in addition to neurology.”
On exam, rheumatologists can assess cranial nerves and strength and reflexes, as well as evaluate for any focal neurologic deficit, Harris added.
In the absence of any available rheumatology professionals, Harris advised that neurologists can ask patients about recurrent fevers, unexplained weight loss, rashes and joint pain and swelling.
“Assessment of a full review of systems is ideal as rheumatology diseases can present with a myriad of symptoms,” she said. “Neurologists should have a low threshold to check screening labs, including inflammatory markers, complete blood count and comprehensive metabolic panel.”
Sorting through all of this information can be a big undertaking, even for two professionals working in tandem. However, every bit of expertise from both rheumatology and neurology is often necessary to manage some of the more challenging patient populations.
For example: dermatomyositis.
Reckoning With Neurological Implications
Dermatomyositis typically presents with sub-acutely progressive, predominantly proximal muscle weakness with or without muscle pain, according to Dimberg.
“Cutaneous manifestations are common, including an erythematous or violaceous rash over the eyelids or malar region, chest or back, or extensor surfaces of the limbs,” he said. “Ragged cuticles and periungual telangiectasias may be seen on inspection of the nail beds.”
An ophthalmoscope can be helpful to visualize these manifestations on exam, he added.
“Severely affected patients can develop swallowing dysfunction or respiratory compromise,” Dimberg said.
Both children and adults can develop this type of dermatomyositis. That said, calcinosis found in the muscular, subcutaneous or connective tissue is more common in children and can be progressive, according to Dimberg.
Additionally, he noted that it is a common misconception that muscle pain, elevated inflammatory markers like erythrocyte sedimentation rate, and elevated creatine kinase levels are necessary for a diagnosis of myositis in general or dermatomyositis in particular, or that an absence of these findings effectively excludes it.
“This is categorically inaccurate,” Dimberg said. “These all may be absent in dermatomyositis in particular, and their absence should not lead the clinician away from the diagnosis.”
Rather, a muscle biopsy is the first step in diagnosing dermatomyositis with neurological implications.
“Biopsy should be of a mild to moderately affected muscle either clinically or on EMG,” Dimberg said. “Diagnostic findings include perifascicular atrophy of muscle fibers with associated structural changes and inflammation in a perivascular and/or perimysial distribution.”
Dermatomyositis also has fairly typical radiographic findings on MRI, which is unusual for most muscle diseases, Dimberg noted.
“T2 weighted imaging shows hyperintensity representing edema involving the subcutaneous tissue and fascia,” he said.
In addition, clinicians should be careful that pathological findings can be the same in juvenile and adult cases.
“They may also be seen in mixed connective tissue disease or SLE,” Dimberg said.
Understanding how rheumatological conditions resemble other conditions is critical for both rheumatologists and neurologists to differentiate it from other potential diagnoses, including CNS lupus.
CNS Lupus Remains ‘Poorly Understood’
In a paper published in Nature Reviews Rheumatology, Schwarz and colleagues wrote that patients with CNS lupus can present with nonspecific symptoms ranging from headache to cognitive impairment. However, patients also may experience “devastating” features, including memory loss, seizures and stroke, the authors wrote.
“Although stroke is one of the more obvious reasons that a neurologist becomes involved in the care of patients with SLE, this is the population I tend to think of with regard to acute onset, or significant worsening, of preexisting depression and other psychiatric conditions,” Allison said.
Although the understanding of neurological complications in SLE has progressed, there is still much to learn, according to Schwarz and colleagues.
“The cognitive and affective manifestations of [neuropsychiatric SLE (NPSLE)], however, remain poorly understood,” they wrote. “Various immune effectors have been evaluated as contributors to its pathogenesis, including brain-reactive autoantibodies, cytokines and cell-mediated inflammation.”
Microglia may be a factor, as may the blood-brain barrier and other neurovascular interfaces, they added.
“As yet, however, no unifying model has been found to underlie the pathogenesis of NPSLE, suggesting that this disease has multiple contributors and perhaps several distinct etiologies,” the authors wrote.
According to Dimberg, it is important to understand that SLE can manifest with either CNS or peripheral nervous system pathology.
“These, in addition to autonomic nervous system and psychiatric disease, are frequently referred to as NPSLE, although CNS disorders predominate,” he said.
The 2019 European League Against Rheumatism/American College of Rheumatology Classification Criteria for Systemic Lupus Erythematosus, published in Arthritis & Rheumatology by Aringer and colleagues, included diagnostic criteria for NPSLE. Delirium, psychosis and seizure are all possible presentations of this condition.
“NPSLE prevalence reaches over 50% in meta-analyses, although cumulative prevalence estimates reach over 90%,” Dimberg said. “CNS presentations, however, are highly varied and may be due to direct inflammation, represent sequelae of secondary causes due to systemic, non-neurologic manifestations of SLE, result from treatment side effects or toxicity, or indicate underlying infection in the immune compromised. All of these must be considered in a patient with SLE in whom CNS symptoms have developed.”
Patients may also develop aseptic meningitis, demyelinating disease, myelopathy or movement disorders, he added.
However, diagnosis using imaging like MRI can be inconclusive in these patients, according to Allison.
“It is not the standard of care to do neuroimaging on patients with depression and anxiety at baseline, but I believe that a significant behavioral change in a patient with a systemic autoimmune condition warrants a deeper investigation,” he said.
To that point, in another paper published in Arthritis & Rheumatology, Hanly and colleagues noted that the ACR has case definitions for 19 neuropsychiatric syndromes in SLE that constitute a comprehensive classification of nervous system events in this disease.
“However, additional strategies are needed to determine whether a neuropsychiatric syndrome is attributable to SLE vs. a competing comorbidity,” the authors wrote. “Cognitive function is a clinical surrogate of overall brain health, with applications in both diagnosis and determination of clinical outcomes.”
Additionally, Hanly and colleagues went on to suggest that ischemic and inflammatory mechanisms are both key components of the immunopathogenesis of NPSLE. This includes abnormalities of the blood-brain barrier and autoantibody-mediated production of proinflammatory cytokines, according to their findings.
As experts continue to wrestle with this inflammatory syndrome, they may find it necessary to manage another difficult patient population — those with neurological complications from vasculitis.
CNS Vasculitis: The Great Mimicker
Leonard H. Calabrese, DO, RJ Fasenmyer Center chair for clinical immunology at the Cleveland Clinic, has been engaged in trying to understand CNS vasculitis for more than 40 years.
“When I started to become interested in CNS vasculitis there were only a few dozen cases ever reported,” Calabrese told Healio Rheumatology, adding that, since that time, interest and research into the disease has grown. “We are now on the verge of establishing CNS vasculitis as the focus of an international collaborative effort to finally bring clarity to the disorder through prospective study, biobanking and ultimately the focus of clinical trials.”
Calabrese has over the years developed a strong collaborative approach to the disease, working with stroke neurologists, immunoneurologists, neuroradiologists and neuropathology, he said. Over the past 2 decades, the clinical program has come under the leadership of Rula Hajj-Ali, MD, of the department of rheumatologic and immunologic disease at the Cleveland Clinic, who now coordinates and leads the care and research effort in a multispecialty clinic dedicated to neurovascular inflammatory diseases.
According to Hajj-Ali, virtually all patients evaluated for possible CNS vasculitis require a “team approach.”
Calabrese added this is vitally important as, “No one is an expert in all the disorders that can mimic CNS vasculitis.”
According to Calabrese, CNS vasculitis is a diagnosis based on clinical evaluation that attempts to define the vascular inflammatory nature of the disease, which most often includes advanced neuroimaging and neurovascular imaging. Furthermore, he emphasized that no work-up for suspected CNS vasculitis is complete without cerebrospinal fluid analysis, which increasingly features the use of next generation sequencing for occult or novel pathogen detection. This may forestall the need for brain biopsy, he added.
If the results of such studies are inconclusive, a brain biopsy should be performed by an “experienced and interested — in benign biopsy techniques — neurosurgeon, and ultimately examined by an experienced neuropathologist,” Calabrese said.
According to both Hajj-Ali and Calabrese, it is critical to rule out mimickers, which most importantly include infection and malignancies that, if missed, can result in catastrophic consequences. Cerebral vasoconstriction syndrome, cerebral involvement of systemic vasculitides or rheumatic diseases, moyamoya angiopathy and infectious vasculopathies should be on the differential.
Virtually all experts interviewed for this story agreed that neurovascular imaging, which includes both direct and indirect angiography, is important but is often plagued by lack of specificity in reaching the diagnosis.
According to Calabrese, the Cleveland Clinic has been pioneering the use of direct vascular wall imaging, which can demonstrate inflammation within the blood vessel wall. This can separate thickening and narrowing from non-inflammatory causes, although it is incapable of determining the etiology, such as whether it is arising from primary vasculitis or an infectious vasculitis, he said.
According to Hajj-Ali, using more powerful imaging devices adds considerably to the resolution, and thus specificity, of the technique, which “has been remarkable when done in a 7 Tesla scanner.” This is now standard to their diagnostic algorithm whenever possible, Calabrese added.
Mind the Headaches
According to Dimberg, another consideration, in the evaluation of primary angiitis of the CNS in particular, is reversible cerebral vasoconstriction syndrome, or RCVS.
This disorder was first described and codified by Calabrese and colleagues in the 1990s and given its current name in a 2007 narrative review — also penned by Calabrese and colleagues — published in the Annals of Internal Medicine.
“Much of the follow-up work refining the understanding of RCVS and its natural history was then taken up by Hajj-Ali, who now has one of the world’s largest experiences with the syndrome,” Calabrese said.
Dimberg added that RCVS is perhaps one of the most common and critically important mimics of CNS vasculitis — and one that does not require immunosuppressive therapy.
“This disorder most frequently presents with thunderclap headache and apparent vasculopathy on angiography with normal brain parenchyma on brain MRI,” Dimberg said. “Brain MRI showing either hemispheric or brainstem infarcts is more consistent with primary angiitis of the CNS.”
To that point, Allison offered a practical tip: Mind the patients who present with headache.
“Within our population of patients with vasculitis impacting the CNS, the patients that do not get diagnosed in an appropriate amount of time are those presenting with headache,” he said. “Once a focal deficit occurs, or encephalopathy begins, the differential diagnosis opens up for most neurologists, but headaches from vasculitis can linger insidiously for some time before other symptoms set in.”
Despite this knowledge, Allison suggested that these patients can still be challenging.
“I am not sure what the solution is when headache is such a common diagnosis that typically does not require neuroimaging,” he said.
Thinking more broadly about CNS vasculitis, Hajj-Alisuggested that understanding this condition is necessary to differentiate it from primary angiitis of the CNS and other such conditions.
“CNS vasculitis mimics multiple diseases, including infections or stroke due to atherosclerotic diseases and many others,” she said.
It is critical to ascertain the exact nature of inflammation in CNS vasculitis as well, according to Hajj-Ali.
“There can be inflammation around the blood vessels for many reasons,” she said. “For it to be CNS vasculitis, the vessel wall has to be invaded by inflammation.”
The best way to determine whether this type of inflammation is present is with a biopsy of the brain, Hajj-Ali added. However, all attempts should be made to make a diagnosis before this step is taken.
“We do not take brain biopsy lightly,” she said.
Hajj-Ali, along with Allison and Harris, enjoy the benefit of joint rheumatology-neurology clinics — a relatively recent development in multidisciplinary care between the two specialties — with all the resources of a major academic medical center at their disposal. For those with access to such resources, it is a development that has proved invaluable.
The Benefits of Working Jointly
Harris offered some thoughts on how a joint rheum-neuro clinic can operate.
“We have two rheumatologists, one neurologist, and two nurse facilitators,” she said. “We also have pharmacy and social work support.”
The site offers a full day clinic once a month, which begins with personalized joint visits with a rheumatologist and neurologist, according to Harris.
“The neurologist and rheumatologist see the patient together and are able to jointly answer questions and discuss the treatment plan,” she said. “Our clinic’s referral process is all internal. Our neurology or rheumatology colleagues directly communicate with the physician leads of our Neurology-Rheumatology Clinic about any patients they think would be eligible and benefit from being served in our specialty clinic.”
In addition, both specialists are required to approve of the patient being seen in this clinic setting before being scheduled.
According to Harris, there are myriad benefits to this system.
“A primary benefit is that the neurologist and rheumatologist see patients together and with dedicated nursing staff we can help arrange imaging studies, infusions, external labs and provide medication education and specific vaccines to this high-risk patient population,” she said. “This clinic also allows for team members in each division to develop expertise in this complex patient population through clinical experience, collaborative discussion, and journal clubs.”
Another site that offers help for clinicians treating rheum-neuro patients is the Cleveland Clinic rheumatology department.
“We developed criteria for CNS vasculitis which are widely employed today,” Hajj-Ali said.
However, not every site has the infrastructure for this type of facility. A byproduct of the physician workforce shortage in the United States is that there are far too many rural — and even suburban — areas where patients may have to travel hundreds of miles to see either a rheumatologist or a neurologist, sometimes in opposite directions.
Relieving the ‘Overbooked’
“One component of my job in our vasculitis clinic is to act as a second opinion and support for clinicians in the broader California community,” Horomanski said. “From the Bay Area, we see people up to the Oregon border and east to Nevada.”
Horomanski co-manages many of the patients with complex vasculitides throughout California, relieving at least some of the stress felt by the few neurology and rheumatology sub-specialists in more rural areas who manage these conditions.
“So many of our colleagues in the community are overbooked and short on time,” she said. “Many vasculitis patients have multi-system diseases with complicated or serious flares. We can work as a team to co-manage these patients to make sure all aspects of their disease are being addressed.”
Although the workforce shortage in neurology does not compare with the one looming in rheumatology, there are many places where there are more patients than physicians, according to Cappelli.
“Telehealth has helped in this regard, but both specialties rely on the physical exam so much, which makes it so much more challenging and complicated to manage some of these patients,” she said.
With that in mind, Cappelli urged both rheumatology and neurology professionals to take advantage of resources published by Hopkins and other major centers. She also suggested that clinicians determine where a patient can get an EMG or a nerve conduction study.
Another suggestion for rheumatologists is that it may be necessary to go back to medical school textbooks to refresh the steps for conducting an effective and comprehensive neurological exam.
“On the education side, we have quarterly conferences that include a large number of cerebrovascular and rheumatology departments along with our vasculitis center,” Hajj-Ali added. “The rise of virtual meetings has enabled us to put together this group.”
To that point, clinicians from anywhere can join the Cleveland Clinic’s meetings and access resources. Participants from as far away as their branch in Abu Dubai have participated in the events, providing a deep well of resources for any rheumatologist or neurologist to use.
Speaking to more clinical topics, Cappelli suggested that finding the source of a patient’s weakness or pain is critical.
“It can help you understand which parts of the neurological system might be affected,” she said.
Horomanski, meanwhile, highlighted her work with trainees, and looked to the future for hope that patients who require joint care from rheumatology and neurology will continue to be managed appropriately.
“One of the most important things I have done is get involved at the trainee level,” she said, noting that she has given a number of lectures to neurology residents. “The more they know about the basics of how to do a workup for these patient populations, the faster we can get them into appropriate care.”
Hajj-Ali also stressed urgency in managing rheumatology-neurology crossover patients, particularly those with CNS vasculitis.
“Knowing how to schedule patients in a timely and efficient manner is critical,” she said. “For so many of these conditions, there should be no delay in diagnosis and treatment.”
- References:
- Aringer M, et al. Arthritis Rheumatol. 2019; doi:10.1002/art.40930.
- Calabrese L, et al. Ann Intern Med. 2007; doi:10.7326/0003-4819-146-1-200701020-00007.
- Hanly JG, et al. Arthritis Rheumatol. 2019; doi:10.1002/art.40591.
- Schwarz N, et al. Nat Rev Rheumatol. 2019;doi:10.1038/s41584-018-0156-8.
- For more information:
- Tyler Allison, MD, and Julia Harris, MD, can be reached at 2401 Gillham Road, Kansas City, MO 64108; email: tallison@cmh.edu; jgharris@cmh.edu.
- Leonard H. Calabrese, DO, can be reached at 9500 Euclid Ave., Cleveland, OH 44195; email: calabrl@ccf.org.
- Laura C. Cappelli, MD, MHS, MS, can be reached at 5200 Eastern Ave., Mason F. Lord Building, Center Tower Suite 4100, Baltimore, MD 21224; email: lcappel1@jhmi.edu.
- Elliot Dimberg, MD, can be reached at 200 First St. SW, Rochester, MN 55905; email: dimberg.elliot@mayo.edu.
- Rula Hajj-Ali, MD, can be reached at 9500 Euclid Ave., Cleveland, OH 44195; email: hajjalr@ccf.org.
- Audra Horomanski, MD, can be reached at 900 Blake Wilbur Dr., Palo Alto, CA 94304; email: ahoroman@stanford.edu; likim@stanfordhealthcare.org.
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