The concept of undifferentiated connective tissue disease (UCTD) was put forward for the first time by LeRoy in 1980, and considered to be the early stage of connective tissue disease (CTD), which could be developed into a specific kind of CTD, or maintained in undifferentiated state without progression [5]. After a long-lasting scientific debate, it is widely accepted that UCTD represent a distinct clinical entity with peculiar clinical findings; the proposed preliminary classification criteria for UCTD include: (1) at least one clinical manifestation of CTDs, (2) positive ANA results, and (3) disease duration of at least three years. However, the criteria may have limitation in making diagnosis, directing treatment and estimating prognosis of those patients with short disease duration no more than 3 years. In fact, although epidemiological data are not available in the literature, up to 50% of the patients with an undifferentiated CTD of less than one year of duration have been reported [6]. Recently, researchers have distinguished two different conditions of UCTD with variable disease course and prognosis, “stable UCTD” and “early UCTD”. Among the division, the so called “stable UCTD” refers to the condition that is up to the traditional criteria as described before and clinically stable over time only with necessarily mild therapeutic intervention. Moreover, the “early UCTD” refers to those patients with recent onset of symptoms and unclassifiable clinical picture which are very likely to progress into a definite CTD in the short time, and it has a crucial clinical importance in term of treatment decision making and disease monitoring [2].

Researches about stable UCTD have revealed that Raynaud’s phenomenon, artralgias/arthritis, skin rash and mild cytopenias are the most frequent onset manifestations; the serological autoantibody profile frequently presents single specificity with ANA positivity highly ranging from 58–90% [1, 7–9]; and after low-dose corticosteroids and immunosuppressive drugs treatment, 70% stable UCTD patients will be maintained in undifferentiated state without progression [6]. Among these stable UCTD patients, severe organ involvements such as heart, renal or neurological manifestations were rarely reported. As far as we know, only 3 cases of CNS involvement in stable UCTD have been reported. Among these cases, two of them were hypertrophic cranial pachymeningitis (HCP), and the other one was reversible posterior leucoencephalopathy syndrome (RPLS). After symptomatic treatment, low-dose corticosteroid or immunosuppression treatment such as azathioprine or methotrexate, all the patients’ symptoms and radiologic abnormalities of brain were improved [10–12]. However, up to now, there is still lack of definite researches about clinical course, prognosis and organ involvement of early UCTD.

In ours case, the increased erythrocyte sedimentation rate, C-reactive protein and titer of antinuclear antibody suggested an active systemic autoimmune disease, but the patient did not meet the existing classification criteria for a certain connective tissue disease, and the disease duration was no more than 3 years. Therefore, the patient was diagnosed as having early UCTD. The lesion on right parietal lobe, presenting hypointensity on MRI T1, hyperintensity on T2 and high signal on FLAIR, was responsible for the onset symptom of left lower limb weakness. The patient declined a cerebral biopsy, but according to the normal intracranial angiogram, the results of CSF study, MRI enhancement and MRS examination, we could exclude the possibility of stroke, cerebral venous sinus thrombosis, NMOSD, MS, autoimmune encephalitis, intracranial infections, and malignant tumors as cause of the lesion. Moreover, examinations in the CNS showed slightly elevated white cell count with increasing percentage of lymphocyte in CSF, and slim contrast enhancement along the surface of swollen gyrus lesion in MRI. Thus, we presumed CNS involvement in this early UCTD patient. After treatment of low-dose corticosteroid and azathioprine, the symptom of left lower limb weakness was almost recovered, abnormalities of immunologic tests and neuroimaging were also greatly improved within a short duration. To our knowledge, the case we described here is the first report of CNS involvement as onset manifestations in a patient with early UCTD.

In summary, CNS involvement may be the onset symptom in early UCTD, and must be recognized early in the presence of systemic blood exam alterations such as high ESR, CRP and ANA, because of good prognosis with prompt and adequate treatment. Diagnosis is difficult as all causative factors must be excluded, and cerebral biopsy is not always feasible. Low-dose steroid and immunosuppressive therapy seems to be effective to the CNS damages in early UCTD, and long-term follow-up is also necessary to investigate the prognosis of early UCTD and CNS involvement.