11/8/2011

Neurological Complications of Sjogren’s Syndrome Julius Birnbaum, MD/MHS Assistant Professor, Division of Rheumatology, Johns Hopkins Hospital Assistant Professor, Dept of Neurology, Johns Hopkins Hospital

No Relevant Financial Relationships with Commercial Interests I will reference an unlabeled or unapproved use of a drug or product in my presentation.

The tortured relationship between MS, neuropsychiatric lupus, and CNS Sjogren’s syndrome

Objectives

In the 1980s, studies reported that clinical patterns and brain lesions in MS versus Sjogren’s patients could be indistinguishable.

(1) Develop a diagnostic and therapeutic approach for demyelinating syndromes.

Editorial in Lancet engendered mass panic, stating that as many as 5 percent of patients with MS actually had undiagnosed Sjogren’s syndrome.

(2) Identify patterns of brain lesions more characteristic of Sjogren’s versus Multiple Sclerosis.

In CNS lupus, such presumed similarity spawned the term “lupoid sclerosis.”

(3) Understand when to institute symptomatic versus immunosuppressive therapy for CNS “focal” disorders of strokes and seizures.

This relationship between MS and Sjogren’s is preserved in disease activity indices, with severe demyelinating attacks regarded as “MS-type” disease. Given the current understanding of MS nearly 30 years after such cohort studies, should we still consider MS as constituting a diagnostic and mechanistic spectrum of demyelinating disease in Sjogren’s patients?

(4) Evaluate how the description of “brain fog” is a phenotype as well as a metaphor, which can help guide current and emerging treatment strategies. (5) Review the entity and diagnosis of small-fiber neuropathy.

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Case I: The scourge of MRI studies in the evaluation of our patients

The scourge of MRI studies in the evaluation of our patients: Evaluating white-matter lesions on brain MRIs with Sjogren’s patients

A 76-year old woman with Sjogren’s, with well-controlled hypertension and hyperlipidemia, complained of dizziness during this past July’s heat wave.

Before the MRI, she was about to enjoy her retirement

She was about to retire from her job as a travel agent, had booked a 6month cruise around the world for her and her husband, and was several weeks away from her 50th wedding anniversary.

“There’s little use for me to be in the middle of the ocean and such a burden to my husband.”

Brain MRI was ordered, with the diagnosis of CNS Sjogren’s syndrome.

After her MRI, this is her response:

“Listen, I’ve gotten all of my affairs in order I just can’t find the right time to break the news to my husband.” “I’m getting ready to put my house on the marker. I’m a very realistic and practical person. How many years to you think I might buy in a retirement community before I need to be in a nursing home?”

The differential diagnosis of brain lesions in a Sjogren’s patients

Next diagnostic steps

“In a patient with Sjogren’s syndrome, the differential diagnosis includes Multiple Sclerosis, vasculitis, Lyme disease, fungal infections, small-vessel vasculopathy, hypercoagulability, small-vessel disease, and non-specific white-matter disease.”

What do we do with the fear of this patient that her husband is imminently going to be a widow?

These differential diagnoses are crippling and frightening to our patients!

Spinal Tap MRI on a 3-Tesla Magnetic Evaluate for disseminated disease, by performing spinal cord MRI Evaluate for disseminated disease, by performing Visual Evoked Potential

Next diagnostic steps:

But in this context, there is an additional diagnostic test which has greater utility than alternative strategies

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How to distinguish MS from Sjogren’s syndrome First, perform the clinical correlate of a bathtub test! Is there any clinical evidence that the patient has ever had a demyelinating disease

TELL HER TO TAKE A BATH! SERIOUSLY!

Secondly, ensure that clinical features and/or MRI patterns are not consistent with the diagnosis of Neuromyelitis Optica Finally, pinpoint whether MRI lesions are more characteristic of MS versus Sjogren’s What follows is such a radiographic potpourri

Distinguishing between Neuromyelitis Optica/NMO versus MS Variables

NMO

MS

Clinical features of myelitis

Motor>sensory

Mainly sensory

Radiographic extent of spinal cord lesions

More than 3 vertebral segments

Less than 3 vertebral segments

Response to interferon medications

Induces relapses

Minimizes relapses

Prognosis of untreated disease after 5 years

50% blind or wheelchairbound

100% ambulatory

Presence of specific MRI or serum bio-markers?

Yes, including the NMO-IgG No antibody

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This pattern of T2 hyperintense, ovoid frontal lesions could potentially be consistent with MS

But in MS, you wouldn’t see this pattern of periventricular sparing

Periventricular lesions which radiate perpendicularly from the ventricular surface: “Dawson’s Fingers”

“Non-specific” periventricular lesions: Seen commonly in Sjogren’s patients, but unfortunately including MS as part of the differential diagnosis.

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Dawson’s Fingers

“Transverse” Myelitis: Can be seen in MS and Sjogren’s

“Transverse” Myelitis: Can be seen in MS and Sjogren’s

The association of myelitis with such a pristine appearance of the brain and other untargeted CNS regions is characteristic of Sjogren’s, and is distinctly atypical for MS

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Distinguishing clinical and radiographic features of MS versus Sjogren’s syndrome Discriminating features

Multiple Sclerosis

Sjogren’s Syndrome

Cerebellar or brainstem involvement

Common

Rare

Optic Neuritis

Common

Only with NMO

Brain lesions at time of spinal cord disease

Almost always

Sparing of brain

Peri-venticular sparing

Rare

Common

Size

Ovoid or punctate

Punctate

Dawson’s Fingers

Specific but not always present

Rare

Bathtub test

Positive

Negative

Bare, naked dread of Sjogren’s patients: Do I have a progressive, neurodegenerative disease?

Allowing phenotypes rather than ancillary testing to propel diagnostic and treatment strategies We have demonstrated how the footprint of clinical phenotypes, should be used as crucibles for evaluating mechanisms and shaping therapies. Why do Sjogren’s patients so invariably and unanimously utilize the metaphor of “brain fog” to describe their experience of cognitive impairment? Similarly to the approach of demyelinating syndromes, can we capitalize on this shared lexicon of brain fog as a phenotype as well as a metaphor?

Take home points about cognitive impairment in Sjogren’s patients

There is a characteristic “A” pattern of deficits seen in “cortical” dementias

Sjogren’s causes subcortical impairment: MMSE is extremely limited

Aphasia, Acalculia, Apraxia, Alexia, Agraphia: Can be assessed on MMSE

Symptoms of brain fog are associated with objective subcortical findings on neuropsychological testing and functional imaging

This is not what Sjogren’s patients convey when they describe “brain fog”

No atrophy on conventional and functional imaging, and is not a progressive, neurodegenerative disease!

Instead, there is a “sludging” of thoughts, difficulty multi-tasking, etc. Fatigue and pain are correlated with selective domains of subcortical impairment.

The absence of “A” deficits means that Sjogren’s patients have subcortical versus cortical impairments in cognitive functioning

Could we encapsulate such a complex interplay between host, immune, and neurobiological responses more elegantly and succinctly than the metaphor of “brain fog”?

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How to appropriately decide whether to institute symptomatic versus immunosuppressive therapy in “focal” CNS disorders, in less than one minute (in almost all cases) Strokes and seizures are considerably less frequent in Sjogren’s versus SLE patients, reported in fewer than 5 to 10 percent of patients.

Does my Sjogren’s patient with strokes and seizures have vasculitis?

Approaching CNS manifestations in Sjogren’s syndrome with clinical equanimity and not fear Multiple Sclerosis in Sjogren’s: A legacy of panic, not a mechanism

No!

Strokes and seizures due to “Vasculitis”: A legacy of panic, not a mechanism We can integrate these findings in activity and damage indices Such refinements may be necessary to ensure the success of promising therapies

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Small-Fiber Neuropathies Associated with Sjogren’s Syndrome

Ann Rheum Dis. 2010 June ; 69(6): 1103–1109

Case II

What is a small-fiber neuropathy?

A 55 year old woman with Sjogren’s syndrome, autonomic neuropathy (tachy-brady syndrome requiring pacemaker, severe gastroparesis), presents with two weeks of following complaints:

A painful, sensory neuropathy which selectively or predominantly affects unmyelinated nocioceptive fibers Clinical examination with preservation of “larger-fiber” modalities

“buzzing” over her left breast “someone sticking an ice pick between my ears” “a caterpillar with sharp claws crawling over both of my thighs” “someone dragging a Popsicle over my calves”

Normal electrodiagnostic studies

Normal EMG and nerve-conduction studies: No “objective” evidence of neuropathy Referred for further evaluation

Take-home point: In context of supportive symptoms and physical examination, “normal” EMG/NCVs may actually support rather than refute a diagnosis of small-fiber neuropathies

Some studies: Require objective evidence of small-fiber dysfunction

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Differential diagnosis of SFNs: The “VITAMIN approach” Epidermis

Epidermis

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Dermis

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Epidermis

* Dermis

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Dermis

Epidermis

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Vasculitis (MPA, Churg-Strauss) Infection: HIV, Hep C Trauma: None Autoimmune Disorders: SLE, Sarcoidosis Metabolic Disorders: Diabetes, 2-hour GGT, Vitamin B12 Inflammatory Disorders: Celiac Sprue, MGUS Neoplasms: Paraneoplastic neuropathies Structural: Exclusionary Diagnoses: Lumbar and cervical canal stenosis, lumbosacral radiculopathy, syringomyelia

Dermis

Don’t forget about plexopathies!

The poetry of Sjogren’s small-fiber neuropathies: Similar to “brain” fog in cognitive impairment, metaphors which are clinical phenotypes “Queen Elizabeth is having a tea party and she’s pouring scalding pints of tea on my face.”

Other potential uses of skin biopsy Enhance sensitivity by analyzing for morphologic changes How can analysis of morphologic changes be interwoven into proposed mechanistic schemes?

“There are these waves of burning pain starting out my spine and moving like a poltergeist and exiting my vagina.”

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Treatment of SFNs Symptomatic control of neuropathic pain Limited case-series have suggested efficacy of IvIG and Rituximab.

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Summary The heart, eloquence, and lyricism that Sjogren’s patients use to describe their symptoms are phenotypes as well as metaphors. It’s time to untangle our conception of MS as intimately intertwined with Sjogren’s. The symptoms of brain fog reflect subcortical versus cortical processes, and are not due to a progressive, neurodegenerative disease. “Focal” CNS disorders of strokes and seizures are almost never due to CNS vasculitis! Cohort studies reporting frequencies of neuropathies less than 5 percent have ignored the entity of SFN. Ann Rheum Dis. 2010 June ; 69(6): 1103–1109

Implications: How to maximize the likelihood that promising therapies will be proven efficacious in therapeutic trials: Mild revision of current activity indices

Acknowledgments

(1) To ensure success of therapeutic trials, we need to potentially limit recruitment of following patients: (a) Patients with strokes and seizures presumed to be due to an active vasculitis but instead due to a “non-inflammatory” vasculopathy; (b) Patients with presumed “MS-type” sensory syndromes which may be due to non-inflammatory dysesthesias and non-inflammatory white-matter lesions.

Research Support NIH P30 grant Accelerated Translational Incubator Pilot grant Johns Hopkins Blaustein Pain Grant Stabler Foundation Grant

(2) We should instead broaden enrollment of to include patients with NMO, and Sjogren’s patients with demyelinating disease which can be discriminated from MS.

Clinical Operations Johns Hopkins Greene Sjogren’s Center Colleagues: Dr. Alan Baer, Dr. Thomas Grader-Beck Our patients!

(3) We may need to broaden enrollment of PNS patients to include SFNs.

Sjogren’s Foundation

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Diagnostic yield of an “Abnormal” skin biopsy “Normal” levels of IENFDs at distal leg: Normative studies have reported IENFDs between 9.8 (+/- 3.6) to 13.8 (+/-6.7) per mm Sensitivity ranges between 50 and 88 percent, depending on whether an “abnormal” skin biopsy is defined categorically as less than 5th percentile of controls (lower sensitivity), or whether defined quantitatively by ROC Specificity ranges between 70 and 95 percent, depending on whether “abnormal” skin biopsy is defined categorically as less than 5th percentile of controls (lower sensitivity), or whether defined quantitatively by ROC Sensitivity is significantly when include evaluation for morphologic abnormalities

“Abnormal” skin biopsies: Issues which affect sensitivity and specificity

Technical Summary of the technique of skin biopsy (1) 3 mm punch biopsy: Risk of complications is 0.12%

(2) Immunostained against PGP 9.5, which is a panaxonal ubiquitin carboxylterminal hydoxylase (3) Processing usually yields approximately 50 vertical, 50 uM sections, with IENFDs counted usually from 3 sections (4) Some heterogeneity in the definition of “normal” IENFDs. Each laboratory should derive values from locally recruited normative controls. (5) High inter- and intra-observer reliabillity (weighted kappa >0.85, but requires intensive training process when a laboratory is first developed)

Why skin biopsy versus alternative and older techniques?

Some heterogeneity dependent on normative values, whether skin biopsy defined qualitatively versus quantitatively

Quantitative Sensory Testing: (QST) Cold, temperature, pain thresholds.

Lower IENFDs seen in males versus females, and increasing age.

Most studies in non-Sjogren’s controls, have reported lower sensitivity and specificity compared to skin biopsies.

How to define “gold standard”

But the sensitivity of QSTs is greatly attenuated in Sjogren’s patients.

Most studies report both sensitivity and specificity which are between 70 percent and 80 percent, when use distal IENFD between 5 and 8 mm

The intensive concentration and cooperation required by QSTs, may be difficulty for Sjogren’s patients with comorbidities associated with neuropathic pain, including impaired cognition and pain.

Some but not all studies can define SFN when there are higher IENFD cut-offs, if there are prominent morphologic findings

BUT, there is likely a very important role for QSTs in the mechanistic evaluation of how neuropathic pain is propagated and amplified in the Central Nervous System (i.e. “central sensitization”) of neuropathic pain.

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Shortcomings of skin biopsy in SS patients Validation studies based on cohorts with “non-inflammatory” SFNS.

Decreased IENFD likely does not cause neuropathic pain Example: In congenital disorder of insensitivity to neuropathic pain, skin biopsy is similar to late-stage diabetics: complete depletion of IENFDs Decreased IENFD likely a surrogate for SFNs due to “dying-back” axonopathy But is such a neurodegenerative surrogate relevant for SS patients?

Role for other functional surrogates of neuropathic pain.

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From the standpoints of our patients, what do we really mean when we talk about a small-fiber neuropathy? We are talking about a clinical presentation of neuropathic pain, which functionally affects smaller-fiber nerves We are not talking about surrogate markers of decreased IENFD We don’t think that Ro/SS-A and/or La/SS-B antibodies are “responsible” for SS Similarly, we should not think that decreased IENFD or other diagnostic biomarkers, are a mechanism of neuropathic pain? What are other mechanisms by which functional perturbations of small-fiber nerves can cause neuropathic pain?

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