Updating the upper reference limits (URL) for cerebrospinal fluid total protein (CSF-TP) according to age may aid in eliminating chances of misdiagnosing chronic inflammatory demyelinating polyneuropathy (CIDP), according to a study published in Muscle and Nerve.

As the standard URL – specified for CSF-TP 45 mg/dL – is increasingly being considered low, investigators evaluated the possibility for stratification of URL standards by age. As a result of concern that an erroneous upper limit contributes to CIDP misdiagnosis, researchers sought to examine how CSF-TP URLs affects sensitivity and specificity of CIDP diagnosis.

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Investigators pooled data from published sources that examined adults diagnosed with CIDP accurately and inaccurately and re-examined them to analyze effect modification for CSF-TP URL. The following CSF-TP URLs were examined for sensitivity and specificity: (a) 45 mg/dL, (b) 50 mg/dL, (c) 60 mg/dL, (d) 50 mg/dL if 50 years old or younger, and (e) 60 mg/dL if older than 50. This analysis included 83 adults, of whom 43% (36/83) did not have CIDP and 57% (47/83) were diagnosed with CIDP.

Among those diagnosed with CIDP, 43 underwent CSF-TP analysis, with a mean value of 105 mg/dL. Of the 36 that were misdiagnosed, 28 underwent CSF-TP analysis, and found to have a mean value of 53 mg/dL. CSF-TP criteria supported diagnosis in cases 12 (33%), of which only 3 fulfilled the clinical criteria for diagnosis. None of these 12 cases met the European Federation of Neurological Societies/Peripheral Nerve Society electrodiagnostic criteria. If URL (a) had been applied, 7 out of these 12 would have been reclassified as normal. Further, 5 misdiagnoses could have been avoided had URL (d) been applied.

In the correctly diagnosed, application of URL (c) and (d) resulted in a reduction in CSF-TP sensitivity from 95% to 84% and 86%, respectively. However, all of them fulfilled electrodiagnostic criteria and had other clinical abnormalities. Although the investigators conclusively found that a modified URL reduced the sensitivity of CSF analysis slightly, the overall CIDP detection rate was unchanged. Also, 12/36 (33%) false positive diagnoses occurred when CSF-TP elevation was used as the sole supportive criteria. By applying the updated URL, the specificity of CSF analysis increased from 39% to anywhere from 57% and 64%.

Limitations of this study included the use of retrospective analysis on a pre-existing cohort and a relatively small sample size.

The investigators concluded that age-stratified CSF-TP URL improved diagnostic specificity of CIDP without compromising sensitivity, thus eliminating chances of misdiagnosis. They recommended heightened caution in those with CSF-TP levels between 45 mg/DL and 60 mg/dL (especially in those >50 years of age). Also, diagnostic caution was recommended when CSF protein was elevated and the clinical and electrodiagnostic symptoms of CIDP were not present or an alternative condition was believed to have caused the elevation.


Breiner A, Bourque PR, Allen JA. Updated cerebrospinal fluid total protein reference values improve CIDP diagnosis [published online April 16, 2019]. Muscle Nerve. doi: 10.1002/mus.26488