SNOWMASS, COLO. (FRONTLINE MEDICAL NEWS) – A lumbar puncture is indispensable when entertaining the diagnosis of primary angiitis of the CNS, Leonard H. Calabrese, DO, declared at the Winter Rheumatology Symposium sponsored by the American College of Rheumatology.

“There’s never an excuse short of an absolute surgical contraindication for not doing a lumbar puncture. It’s amazing to me how often this heuristic is overlooked. Virtually all patients with biopsy-proven CNS vasculitis have an inflammatory spinal fluid. This gets you into the club. I always have great unease when I’m seeing a patient – no matter what else I’m seeing that suggests this condition – if the spinal fluid is totally pristine. This does not happen very often at all,” said Dr. Calabrese , professor of medicine and vice chairman of the department of rheumatic and immunological diseases at the Cleveland Clinic in Ohio.

Primary angiitis of the CNS (PACNS) is a rare disorder with a dizzying array of mimickers.

“Not many of us in rheumatology take care of these patients on a regular basis, but the question of whether a patient has CNS vasculitis is actually pretty common. If you do any kind of hospital consultation work, you’ll get called onto the neurology unit to evaluate an obtunded patient with multiple strokes,” he observed.

Neurologists know a lot more about the brain, yet they often seek input from rheumatologists, who are typically much more familiar with the heavy-hitting drugs used in treating PACNS.

In an influential paper published nearly 3 decades ago, Dr. Calabrese and a colleague proposed diagnostic criteria for PACNS which still hold up today. They defined the disorder as a neurologic deficit that remains unexplained after a vigorous diagnostic work-up accompanied by either a high-probability angiogram for vasculitis or biopsy evidence of CNS vasculitis along with exclusion of all conditions capable of either mimicking the angiographic features of arteritis or producing secondary arteritis ( Medicine [Baltimore]. 1988 Jan;67[1]:20-39 ).

Mimickers of PACNS include systemic inflammatory conditions such as Sjögren’s, systemic vasculitis, sarcoidosis, and paraneoplastic conditions, all of which a rheumatologist can typically rule out at the bedside. Other mimickers include coagulation disorders, infections, demyelinating disorders, CNS lymphoma, reversible cerebral vasoconstriction syndromes, and an ever-expanding list of genetic disorders.

“There is no one in the world who’s an expert on all these diseases, so it’s very important for us to work interprofessionally,” the rheumatologist stressed.

At the Snowmass meeting, Dr. Calabrese presented his seven heuristics – that is, loosely defined rules or mental shortcuts – for getting the diagnosis right.

• PACNS can never be securely diagnosed based solely on clinical findings

The findings with the highest pretest probability of PACNS are chronic meningitis for more than 3 weeks, multiple strokes, or unexplained strokes with poststroke cognitive impairment.

Less specific findings in patients with PACNS may include headaches, behavioral changes, encephalopathy, focal sensorimotor abnormalities, ataxia, scotoma and other visual changes, radiculopathy, and myopathy.

• Don’t skip the lumbar puncture

The cerebrospinal fluid (CSF) is abnormal in more than 95% of patients with PACNS. The findings usually are consistent with aseptic meningitis, with modest pleocytosis, elevated protein levels, and a normal glucose.

• Nonvascular imaging is highly sensitive but has low specificity for PACNS

Thus, nonvascular imaging can’t confirm the diagnosis.

“I don’t believe patients can have this diagnosis with a normal MRI with gadolinium enhancement and diffusion-weighted imaging. With true vascular inflammation and parenchymal destruction, something will be seen. So in a patient who has a headache and can’t think properly but has a pristine MRI, it’s probably not this disease, and it’s time to move along,” according to the rheumatologist.

• No angiographic study has 100% specificity for the diagnosis of PACNS

“No one can tell you ‘This is vasculitis’ from an angiogram, just like no one can tell you an abnormal chest x-ray is always pneumonia. While an angiogram can be very, very suggestive, the specificity drops off in small-vessel disease,” Dr. Calabrese said.

• Don’t fear brain biopsy

Brain biopsy is clearly underutilized. It’s a valuable yet imperfect diagnostic tool.

“A well-done biopsy by a good neurosurgeon who’s interested in CNS vasculitis and works interprofessionally probably has greater than 80% sensitivity and 90%-100% specificity for PACNS,” according to Dr. Calabrese.

The brain biopsy is not only helpful in ruling in the diagnosis of PACNS, it’s also an excellent tool for identifying rule outs. In one study, mimickers of PACNS were identified by brain biopsy in 39% of patients.

“You find something else about 40% of the time – and that’s a good thing,” he said.

Physicians who have difficulty getting a patient or family to okay a brain biopsy are generally going about it wrong, Dr. Calabrese continued.

“I can’t think of a single instance in all my years of practice where a patient has refused a brain biopsy after we’ve engaged in a shared decision-making process. Why? Because I tell them I think it’s important. This is a grave diagnosis with a tremendous impact for the patient. It involves serious therapies and a guarded prognosis,” he explained.

“Often the prospect of brain biopsy is presented to the patient as just the worst thing in the world that could happen to them: ‘They’ll take a piece of your brain. You’ll lose your piano lessons.’ When actually there’s good evidence that biopsies taken in the absence of brain edema involve minimal morbidity and virtually no mortality,” he noted.

• Mind the must-rule-outs

“Ask yourself,” Dr. Calabrese said, “‘What’s the worst thing that could happen here if I goof up this diagnosis?’”

The answer is the worst that can happen is that a CNS infection or malignancy gets misdiagnosed as PACNS. Those are the two must-rule-outs: infection – be it viral, tuberculosis, fungal, syphilis, bacteria, parasites, or Rickettsia – and malignancy.

“Malignancies can be insanely complex. Five percent of solid tumors will have leptomeningeal metastasis and present with chronic meningitis; that’s always goofing us up,” Dr. Calabrese said.

Intravascular CNS lymphoma is an important mimicker of PACNS. The affected patient may have headaches, punctate infarctions upon imaging, an abnormal CSF, and a mildly abnormal angiogram. The only way to distinguish it from PACNS is by brain biopsy.

“CNS lymphomas are always angiocentric, so unless you’ve got a really good pathologist and a really good biopsy specimen you may goof this up,” Dr. Calabrese cautioned.

• Failure to respond to cytotoxic agents and glucocorticoids suggests an alternative diagnosis, not refractory disease

It’s very unusual for a patient with PACNS to fail a robust course of cyclophosphamide or methotrexate plus steroids. This is a red flag situation warranting a pause to reconsider the diagnosis.

Other red flags commonly encountered by a consulting rheumatologists are that a neurologist diagnosed PACNS in the absence of a lumbar puncture, or on the basis of angiographic findings with a normal CSF.

Dr. Calabrese reported having no financial conflicts of interest.


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