Clinical manifestations

Presentation and course

Patients with CLIPPERS present with subacute brainstem symptoms--most often ataxia, diplopia, dysarthria, and altered facial sensation (33; 42; 54). Less common brainstem features include pseudobulbar affect, tinnitus, nystagmus, facial palsy, dizziness, nausea, hiccups, and palatal myoclonus (33; 38; 42). Other features may include long-tract signs, including paraparesis, sphincter dysfunction, and cognitive dysexecutive symptoms (33; 38; 42; 05). The latter correspond to the presence of gadolinium enhancement in regions adjacent to the primarily affected brainstem.

Without treatment, symptoms progress, and relapses are common. In a study of 12 patients with CLIPPERS, the annualized relapse rate was 0.5 (0.25 to 2.8), with a mean residual EDSS score of 1.9 (range 0 to 7). Relapses seemed to occur when oral prednisone dosage was titrated below 20 mg per day, but patients responded well to an increase of corticosteroids (42).

Diagnostic criteria are proposed based on an assessment of 35 patients with a presumed diagnosis of CLIPPERS, of whom 23 were ultimately diagnosed with this disorder (Table 1).

Table 1. Proposed Diagnostic Criteria for CLIPPERS

The accuracy of the proposed diagnostic criteria was later evaluated (44). Forty-two patients were followed for a median of 50 months. The sensitivity of the CLIPPERS criteria was 93%, and the specificity was 69%. There were 13 mimics in 42 patients (later confirmed to have systemic and central nervous system lymphomas, primary central nervous system angiitis, and autoimmune gliopathies).

Prognosis and complications

Knowledge about the complications associated with CLIPPERS is limited. Complications may include weight loss, aspiration pneumonia, dysarthria, spasticity, urological complications (residual urine, incontinence, infection), and decubitus. Complications often require a multidisciplinary approach involving dietitians, speech therapists, physiotherapists, and psychologists.

Clinical vignette

A 58-year-old woman had a 4-week history of subacute gait ataxia, dysarthria, and paresthesia of the face, hands, and feet. She had four relapses during the follow-up period from 2007 to 2013. Serial MRI revealed multiple small contrast-enhancing lesions progressively involving the brainstem, the mesencephalon, and, to a lesser degree, the subcortical white matter.

She was treated with steroids and steroid-sparing agents (eg, azathioprine) and responded clinically and radiologically but relapsed on each tapering.

When she was diagnosed with CLIPPERS in 2012 (ie, 2 years after the first description of this disorder), she was put on maintenance immunomodulatory treatment, which was subsequently tapered to 5 mg prednisolone once daily together with azathioprine (2.5 mg/kg bodyweight). She did not experience further relapses but remained severely dysarthric and ataxic. Neuroimaging no longer showed any contrast-enhancing lesions, but there was remarkable cortical cerebral and cerebellar atrophy.

Biopsy revealed parenchymal and perivascular inflammatory infiltrates predominantly composed of CD3 + T cells and CD68 + microglia/macrophages. Repeated CSF analysis showed mild lymphocytosis but no oligoclonal bands. Ten years after presentation, the patient was severely dysarthric, moderately cognitively impaired, and wheelchair-bound and had mild involuntary choreiform movements of tongue and hands (modified Ranking scale 4).

Biological basis

Etiology and pathogenesis

The etiology of CLIPPERS is not known.

Based on MRI findings, neuropathology, and response to steroids, CLIPPERS is believed to be inflammatory. Biopsies from affected areas show a predominant perivascular infiltration of CD3+ T cells (33). Most of these are CD4+ T cells, whereas CD8+ T cells, B-cells, and plasma cells are seen in a smaller number (33; 48). A few cases with more predominant perivascular B cells infiltration was described (52). CD68+ histiocytes can be present in moderate numbers, as well as infiltrating macrophages (38; 48). A small number of neutrophils and eosinophils was found in some cases (42; 48). There is also a suggestion that CLIPPERS is mediated by Th17 cells (28). Reactive gliosis and signs of neurodegeneration with variable axonal injury (axonal spheroids and torpedoes) are seen in some specimens (38; 05; 48). This neurodegeneration can be associated with diffuse demyelination, but focal demyelinating lesions, as seen in multiple sclerosis, are not found (48). Demyelination may be secondary to massive inflammation and neurodegeneration. The neuropathological findings in CLIPPERS are generally correlated to the inflammatory pattern seen on MRI but are also found to a lesser extent in regions with normal MRI appearance (05).

A few cases in the literature have suggested autoimmunity secondary to viral infections, such as hepatitis B (50), Epstein-Barr virus (26), or HSV3 (51) or even following Influenza vaccination (16; 51; 35).

Pathological examination is especially important to rule out CLIPPERS mimics in cases with atypical clinical or radiological features. There are no signs of vessel wall destruction with fibroid necrosis, as seen in vasculitis. Aggregates of histiocytes may resemble loose granulomas but without peripheral lymphocytic cuffing or necrosis, and granulomas generally do not occur (38; 48). Moreover, no light chain restriction or other features of lymphoma are present (05).

The suspected inflammatory nature of CLIPPERS is further substantiated by a number of cases with often transient CSF-specific oligoclonal bands. A target antigen in microstructures within the perivascular space has been proposed (33). Others argue for the role of T cell-mediated cell death (42). Activation and deposition of complement and IgG were observed in a few biopsy-confirmed cases (04).

A possible allergic mediator was proposed due to the elevated serum IgE level in some patients (19). None of these potential mechanisms have been confirmed.

Because some symptoms and signs of CLIPPERS are common features of a variety of diseases, it is not uncommon for patients initially diagnosed with CLIPPERS to be subsequently diagnosed with other disorders. Lymphoma cases are the most commonly described (08; 24; 45; 25; 14). Interestingly, a case of lymphoma in a patient also diagnosed with CLIPPERS was seen in the latest and largest case series (48). CLIPPERS is, thus, a potential premalignant state. Although most cases do not develop malignancy even after a prolonged follow-up (05; 48), hyperreflexia, elevated protein in CSF, and recurrences less than 1 year after treatment or while on high-dose maintenance steroids are risk factors suggesting an underlying lymphoma (55). Patients with lymphoma tend to have a worse prognosis than those without lymphoma.

The genetics of CLIPPERS are as yet unknown, and no familial clustering has been described thus far. However, in a small study conducted in 12 patients with probable or definite CLIPPERS, one third had HLH gene mutations (PRF1 and UNC13D mutations) (43).

Epidemiology

The incidence and prevalence of CLIPPERS are unknown. Since the original description in 2010 (33), more than 140 cases have been reported. Some of these have features that are atypical (large asymmetrical lesions, mass effect, etc.) and do not fulfill the proposed diagnostic criteria (Table 1) (48). The disease could be missed if MRI is done without gadolinium enhancement. With more than 100 cases worldwide over the past 13 years, the disease must be considered rare. CLIPPERS was initially thought to affect males and females equally, but in the larger case studies, the male-to-female ratio is approximately 3:1 (42; 48).

Differential diagnosis

A wide range of diseases with brainstem features that mimic CLIPPERS and are provided in Table 2, together with features that may help distinguish these conditions.

Table 2. Differential Diagnosis in CLIPPERS

Lacking a specific biomarker in CLIPPERS, there is a potential risk of overdiagnosis. This is suggested by the numerous case descriptions of CLIPPERS mimics. Several diseases can present with punctate or curvilinear MRI changes (41), and a number of red flags were proposed. A careful examination for alternative causes should be performed (54). Red flags include (1) no response to corticosteroids or relapse on a daily dose of prednisone/prednisolone greater than 30 mg, (2) acute onset or progression, (3) lack of brainstem-prominent features, (4) signs of systemic disease, (5) peripheral nervous system involvement, (6) normal brain MRI, (7) significant asymmetrical lesions, and (8) severe edema or mass effect on MRI. Red flags may occur up to 18 months after disease onset (44).

Common mimics of CLIPPERS are: CNS lymphoma, CNS vasculitis, multiple sclerosis, and neurosarcoidosis. Most of these diagnoses may be distinguished based on MRI findings. In CLIPPERS, the punctate lesions are usually small (less than 3 mm) and not confluent, and the T2 hyperintensity does not significantly exceed the gadolinium enhancement. No ring enhancement is seen. Careful repeated examination of CNS cell components with cytology and flow cytometry helps differentiate from lymphoma. Brain biopsy can be needed in cases that have atypical features.

Paraneoplastic disorders, intraparenchymal brainstem metastases, and primary brainstem gliomas should also be considered (18). The latter often have mass effect or significant edema on T2-weighted imaging.

Behçet disease often has brainstem features. The absence of oral and genital ulcers, lack of uveitis and erythema nodosum, and negative HLA-B51 are helpful for distinction (01).

Bickerstaff brainstem encephalitis is part of the spectrum of Miller-Fisher syndrome. Besides ataxia, it may present with peripheral involvement (areflexia); most cases (80%) are associated with anti-Gq1b antibodies. Imaging is often normal or shows nonenhancing brainstem T2 hyperintensities (37).

Langerhans histiocytosis X involves the hypothalamus, causes lung lesions, and has more confluent lesions on MRI.

Polyostotic sclerosing histiocytosis (Erdheim-Chester disease) includes bony lesions, diabetes insipidus, and infiltrative lesions with meningeal involvement on MRI (22).

Infectious causes of rhombencephalitis, such as listeria, enterovirus 70, herpes viruses, and tuberculosis, should also be considered (18). Most of these can be excluded by careful CSF examination, including virus PCR, fungal smear, and bacterial and fungal culture.

Anti-GFAP astrocytopathy has been described as an autoimmune meningoencephalitis. Patients often have prominent headache, papillitis, and medullopathy (11; 53). MRI shows supratentorial linear perivascular enhancement on MRI and anti-GFAP IgG in serum/CSF.

Myelin oligodendrocyte glycoprotein (MOG) autoimmunity can mimic CLIPPERS (39; 02; 30; 12; 15). However, it usually can be differentiated from CLIPPERS by the presence of MOG-IgG antibodies, the involvement of the optic nerves, and inflammatory lesions in the spine and conus medullaris.

A proposed diagnostic workup to help differentiate CLIPPERS from alternative causes is provided in Table 2.

Diagnostic workup

Table 3. Diagnostic Workup in CLIPPERS

A careful medical history should be obtained, including signs of systemic abnormalities (uveitis, sicca syndrome, arthritis, fever) and a history of oral or genial ulcers.

Initial investigation should incude brain MRI and, in cases with medullopathy, also spinal cord MRI. MRI should be gadolinium-enhanced with imaging of vasculature. The MRI hallmark of CLIPPERS is punctate or curvilinear gadolinium enhancement, predominating in the pons and with possible involvement of adjacent regions of the cerebellar peduncles, cerebellum, medulla oblongata, and mesencephalon.

Gadolinium enhancement can extend into the cervical and, less commonly, thoracic medulla.

Supratentorial involvement of the basal ganglia and subcortical white matter and cortical hemispheres can be seen (48). High-field MRI may help demonstrate lesions in regions with normal-appearing brain matter (05). Punctate lesions are usually small (less than 3 mm) and tend to be smaller when found in adjacent regions (33). Larger confluent lesions or asymmetrical lesions were described but are not common and should prompt a careful examination for alternative causes. Slight hyperintensities are seen on T2, but importantly these do not typically exceed the size of gadolinium enhancement (33; 48). Lesions with severe edema or mass effect are not seen and should prompt consideration of malignancies, such as metastases or glioma.

Use of other MRI sequences, such as SWI or PWI, was suggested, but their utility is not yet confirmed (32). Evaluation of available DWI imaging in 22 patients with CLIPPERS found only one patient with minor DWI high signal (48). With multiparametric and quantitative methods, another case showed a decrease in regional cerebral blood flow and cerebral blood volume on perfusion-weighted imaging, as well as elevated density of tracts and a decrease of fraction anisotropy in the pons on diffusion tensor imaging (21).

Cerebral angiogram (MRI or CT angiogram) is important to help exclude cerebral vasculitis. Angiograms are normal in CLIPPERS.

An important feature of CLIPPERS is the prompt clinical and radiological remission with corticosteroid treatment. Clinical remission follows the radiological remission (33). If gadolinium enhancement shows no remission after treatment, alternative diagnoses should be considered (48).

Follow-up MRIs are important in cases of relapse. Atrophy of pons and cerebellum is sometimes seen with prolonged follow-up.

No blood or CSF biomarker is available for CLIPPERS. Extensive laboratory testing is needed to help distinguish CLIPPERS from other causes. A suggestive panel of tests is outlined in Table 3. These include complete blood count, tests for systemic and paraneoplastic antibodies, hepatitis and HIV screening, and tests for specific inflammatory conditions (anti-MOG, Anti-GFAP and Anti-Gq1b). Elevated serum IgE was found in some cases (38). Similarly, ANA, ds-DNA, and SSA/SSB were found in some cases but without clinical correlation to a specific syndrome (33; 38). The significance of these is unknown.

CSF analysis is important in all patients with suspected CLIPPERS. The most common pathological feature seen is a mild protein elevation (44 to 114 mg/dl). Some cases have a slightly elevated lymphocytic pleocytosis (9 to 114 cells ul/L), but a marked pleocytosis should raise concern for an alternative cause. Oligoclonal bands are occasionally seen and are often transient (42; 41). CSF analysis is important for the exclusion of infection (Table 3), and cytology and flow cytometry is recommended as CNS lymphoma may mimic CLIPPERS.

Whole-body PET-CT or CT of thorax and abdomen can help exclude underlying malignancy with intracerebral metastases or paraneoplastic conditions but may also help diagnose systemic inflammation in neurosarcoidosis or rheumatological disorders. Biopsy of changes found on whole-body imaging is recommended.

Brain biopsy in CLIPPERS remains somewhat controversial. Reports of lymphoma mimicking CLIPPERS have led some to recommend brain biopsy in all patients suspected (23). Pathology findings are, however, not specific for CLIPPERS and should be used to rule out other causes. Even though brain biopsy in regions typically affected by CLIPPERS is complicated (eloquent areas: brainstem, cerebellum, and spinal cord), it should be considered in patients with atypical findings. Brain biopsy should target an atypical enhancing lesion when noninvasive investigations remain inconclusive (44). Typical cases of CLIPPERS can be diagnosed to a probable level without brain biopsy (Table 1) (48).

Management

Treatment of CLIPPERS is based on case series and individual case reports. No randomized controlled trials are currently available due to the rarity of the condition. Treatment should be started early (48).

Initial treatment. High-dose intravenous corticosteroids (1 g intravenous methylprednisolone daily for 3 to 5 days) are recommended (42; 48; 54). In some cases, treatment was expanded to 10 days when no clinical effect was seen. This should be started in conjunction with early use of high-dose hormone pulse therapy. Clinical remission is usually seen within days. Prednisone (1  mg/kg per day) or six courses of cyclophosphamide and azathioprine or immunoglobulin did not improve clinical symptoms during an attack (40).

Chronic treatment. Patients should be continued on oral corticosteroid (1 mg/kg prednisone) with a very slow taper (eg, 5 mg per week to 20 mg) (48). Alternatively, oral prednisone can be started at a dose of 1  mg/kg/d for 4 to 8 weeks, then tapered by 10 mg every 2 weeks to 20 mg/day, then 2.5 mg every 4 weeks to 10 mg, then 1 mg every 4 weeks until 5 mg/day (40).

Relapse is common while tapering corticosteroids but usually occurs at doses less than 20 mg daily (42). The addition of a steroid-sparing agent should be considered when starting oral corticosteroids (54). However, these are often insufficient in monotherapy, and continuous oral corticosteroid treatment is often necessary (10).

Steroid-sparing agents in doses higher than the ones used for rheumatological conditions are often needed (48). Used agents include azathioprine (2.5 mg/kg/day), methotrexate (target dose 22.5 mg weekly), and mycophenolate mofetil (2 g per day divided in individual doses) (54).

Treatment with prednisone above 20 mg/day should be maintained until the steroid-sparing agent is effective. Relapse during or after cessation of immunotherapy should be treated with repeated high-dose intravenous corticosteroid (54).

The efficacy of anti-CD20 treatment with rituximab was described in some cases, even though only a limited number of B cells were seen in the lesions (42; 07). This is in line with increasing evidence that B cells are important regulators of T cell function. Intravenous immunoglobulins appear ineffective (13). Hydroxychloroquine was reported effective in one case and ineffective in others (33; 46). Antituberculous therapy was reported in one case, but efficacy was not confirmed (28). Chronic treatment with leflunomide was effective in one case (09) as well as chronic treatment with cladribine in another case (47). Treatment with tacrolimus and tocilizumab was also trialed successfully in another case (34).

No data on the length of treatment are available. Some recommend treatment for 12 months before withdrawing immunotherapy (54). MRI follow-up should be performed after treatment cessation as MRI findings may precede clinical symptoms. Further studies are needed to determine the most efficient chronic treatment.

Cautions and side effects. With prolonged high-dose corticosteroid treatment, additional prophylactic agents, including PCP prophylaxis, calcium with vitamin D, and proton pump inhibitors, are needed. Bone densitometry testing is recommended. Treatment with bisphosphonate may be necessary if osteoporosis is present or occurs during treatment. Monitoring for hyperglycemia is recommended. Abrupt discontinuation of steroids should be avoided due to the risks of Addison crisis.

Intravenous methylprednisolone often causes psychosis, hyperglycemia, and insomnia. Additional side effects seen more commonly with long-term oral prednisone include infection, osteoporosis, avascular necrosis of the hip, Cushingoid appearance, skin thinning and easy bruising, depression, cataracts, hypertension, weight gain, and edema.

Blood monitoring is necessary for patients taking steroid-sparing immunosuppressants. Laboratory testing for complete blood count, renal function, and liver function should be performed before the initiation of treatment and then once weekly for 1 month, twice weekly for 1 month, and monthly thereafter for the duration of treatment with methotrexate or azathioprine.

With methotrexate treatment, folic acid supplementation is needed. Methotrexate may result in myelosuppression, nephrotoxicity, liver damage, pulmonary fibrosis, toxic epidermal necrolysis, and an increased risk of infection.

Mycophenolate mofetil is associated with infection, increased risk of malignancy (lymphoma, skin cancers, and others), diarrhea, hypertension, hepatitis, myelosuppression, and renal failure. Mycophenolate mofetil use may be limited by high cost.

Before starting azathioprine, testing thiopurine-S-methyltransferase (TPMT) activity is necessary, as patients with low enzyme activity are at increased risk of toxicity from the drug. Azathioprine is associated with infection, malignancy (lymphoma, skin cancers, and others), nausea, macrocytic anemia, skin rash, hypersensitivity reaction, pancreatitis, and elevated liver function tests.

Rituximab may cause infusion reactions and increase the risk of infection (including progressive multifocal leukoencephalopathy); it may increase the risk of hematological malignancy and may cause hypotension and gastrointestinal perforations. With rituximab, some recommend periodic monitoring of the CD19 count every 6 to 9 months and consider another round of rituximab only if CD19 cells have been replenished or clinical deterioration occurs, whereas others base this decision on clinical factors alone.

Corticosteroids and steroid-sparing immunosuppressants are associated with a wide range of side effects.

Side effects associated with cyclophosphamide include infection, increased risk of malignancy (lymphoma, skin neoplasms, and others), nausea and vomiting, hemorrhagic cystitis, alopecia, and infertility.

Outcomes

CLIPPERS is a progressive brainstem syndrome with an often-dramatic response to corticosteroids. The majority of patients have some residual disability after treated relapses (EDSS of 1.9) (42). Relapses are common, especially with corticosteroid doses less than 20 mg/day. In a study of 12 patients, the annualized relapse rate was 0.5 (0.25 to 2.8 without long-term corticosteroid treatment) (42). Some patients progress even with aggressive immunotherapy (48). Even after multiple attacks, most patients had only moderate disability and remained ambulatory at the last follow-up (Median EDSS of 3) (42). In a retrospective study of 23 CLIPPERS patients with a median follow-up of 44 months, the median mRS was 1 (48). Five patients were dead at follow-up (median 27 months from symptom onset) due to sepsis (n=2), systemic B cell lymphoma (n=1), progressive neurologic disease (n=1), and uncertain cause (n=1).

Special considerations

Pregnancy

No information is available concerning pregnancy in patients with CLIPPERS. Steroid-sparing agents can be teratogenic and are not recommended.