Abstract
Background
Chronic lymphocytic inflammation with pontine perivascular enhancement responsive to steroids (CLIPPERS) is an inflammatory central nervous system disorder, typically presenting with subacute symptoms referable to brainstem and cerebellar pathology. This is the first report of CLIPPERS presenting with a painful trigeminal neuropathy.
Case report
We report an unusual case of CLIPPERS presenting with facial pain and sensory symptoms, in the absence of other brainstem or cerebellar signs. Perivascular enhancement of peri-pontine structures on neuroimaging, lymphocytic infiltrate on histopathology and rapid clinical and radiological responsiveness to glucocorticosteroids were key to diagnosis. Extensive investigations excluded various differential aetiologies.
Conclusion
The pathogenesis of CLIPPERS is poorly understood, and the diagnostic criteria are yet to be validated. In this case, facial pain was not associated with other brainstem or cerebellar signs, broadening current understanding of how CLIPPERS may present. This has clinical implications in guiding future investigations for patients presenting with painful trigeminal neuropathy.
Keywords
Introduction
Chronic lymphocytic inflammation with pontine perivascular enhancement responsive to steroids (CLIPPERS) is a rare inflammatory neurological disorder that typically affects the brainstem, particularly the pons and cerebellum (1–3). In an analysis of 23 patients with CLIPPERS, Tobin and colleagues (1) reported a median age of disease onset of 58 years (range 33–86), which is in keeping with other reports (3). The male: female ratio of CLIPPERS is approximately 2.2:1 (1,3). It characteristically presents with symptoms and signs such as diplopia, nystagmus, dysarthria and ataxia, consistent with the predominance of brainstem and cerebellar pathology. Whilst altered facial sensation has been reported previously, this has typically occurred as part of a constellation of symptoms, rather than as the primary presentation (3). Occipital headache has also recently been reported as a presenting symptom in association with the more classical signs of gait ataxia and dysarthria (2). To the authors’ knowledge, there have been no previous cases of CLIPPERS presenting with facial pain due to painful trigeminal neuropathy as the primary complaint.
The diagnosis of CLIPPERS is based on clinical, radiological, and histopathological correlation and the exclusion of other disorders (1–3). Magnetic resonance imaging (MRI) in CLIPPERS characteristically shows punctate and/or curvilinear, predominantly perivascular, gadolinium enhancement of the pons and peri-pontine structures, particularly the cerebellum, described in the literature as “peppering” (3). Supratentorial and spinal cord lesions are reported less frequently (1,3). Histopathologically, CLIPPERS is characterised by a predominantly T cell lymphohistiocytic infiltrate (4,5). Rapid clinical and radiological responsiveness to glucocorticosteroids is considered core to the diagnosis, with symptoms almost always recurring after steroid withdrawal (1,3). The pathogenesis of CLIPPERS is poorly understood but is thought to be autoimmune, or otherwise, inflammation-mediated (3). Specific serum or cerebrospinal fluid (CSF) markers are yet to be identified and diagnosis requires extensive investigations to exclude differential diagnoses (3,4).
Case report
A 56-year-old previously well female presented with a 10-day history of right-sided facial paraesthesias and pain. These were associated with a right occipital throbbing headache with nausea and vomiting. The headache was rated as 3/10 in severity by the patient and would occur intermittently, lasting up to 30 minutes at a time. It was made worse by head movement and vomiting. The headache resolved spontaneously after 3 days, but the facial paraesthesias and pain persisted. The paraesthesias started as tingling over the right scalp and temple, which spread over the upper and lower jaw and then inside the mouth. The tingling was later replaced by persistent numbness. The facial pain was the most debilitating symptom. It was constant, affecting the V2, and V3, divisions of the trigeminal nerve, including the anterior part of the right ear. The pain was exacerbated by exposure to the wind and cold. It did not respond particularly well to oral analgesics, including opiates, and the patient was started on gabapentin 300 mg three times a day and amitriptyline 10 mg at night with significant improvement. Light touch tested with cotton wool, and pinprick sensation tested with a Neurotip, were diminished in the right V2 and V3 trigeminal divisions, but the corneal reflex was preserved. Thermal sensation was not formally tested. There was brush allodynia in response to light touching of the affected area of the right ear with cotton wool. No other focal neurological deficits – in particular, no cerebellar signs – were identified. This was on a background of Hashimoto’s disease, with no personal history of migraine or any other significant medical, family, or psychosocial history.
Magnetic resonance imaging of the brain and spine performed 12 days after the initial onset of symptoms demonstrated abnormal foci of enhancement (Figure 1(a), (d), (g)), as well as increased T2 flair hyperintensity, in the right inferior cerebellar hemisphere, brachium pontis and pons, with similar, less marked changes in the upper cervical cord (Figure 1(d)). There was also striking enhancement of the right trigeminal nerve in the pons, at the dorsal root entry zone (DREZ) and in its cisternal segment (Figure 1(a), (g)). The impression was of a possible malignant, inflammatory or, less likely, infective process, with a broad range of differentials including: Lymphoma; metastatic malignancy; sarcoid; connective tissue disorder (CTD); cerebral vasculitis; and multiple sclerosis (MS). Various investigations to exclude these aetiologies (Table 1) yielded either negative or non-specific results, apart from a modestly elevated positive antinuclear antibody titre of 1:320 and low-level erythrocyte sedimentation rate of 18 mm/hr. Oligoclonal bands (OCBs) were detected in CSF, but not serum. Computed tomography (CT) of the chest/abdomen/pelvis demonstrated no evidence of lymphadenopathy or organ involvement. Whole body positron emission tomography (PET) showed focal increased fluorodeoxyglucose (FDG) uptake exclusively in the known right cerebellar and cervico-medullary junction lesions.
MRI findings at different time-intervals. Axial ((a)–(c)), coronal ((d)–(f)), and sagittal ((g)–(i)), post gadolinium enhanced, T1 weighted MR images. MRI prior to treatment ((a), (d), (g)), demonstrates punctate, and curvilinear, foci of abnormal enhancement in the right inferior cerebellar hemisphere, brachium pontis and pons, with an additional focus of enhancement in the right C2 segment of the spinal cord ((d), arrow). There is marked enhancement of the right trigeminal nerve in the pons, at the DREZ and along its cisternal segment (arrows, (a), (g)). Repeat MRI 2 weeks post treatment shows dramatic reduction in the abnormal enhancement in all previously affected areas ((b), (e), (h)), while follow-up MRI, done 3 months after initial treatment, shows complete resolution of the abnormalities ((c), (f), (i)). Serum and cerebrospinal fluid laboratory investigations. ANA: antinuclear antibody; ANCA: anti-neutrophil cytoplasmic antibody; ACE: angiotensin converting enzyme; ENA: extractable nuclear antigens; CRP: C-reactive protein; ESR: erythrocyte sedimentation rate; EPG/IEPG: electrophoresis and immunofixation; NMO: Neuromyelitis Optica; PCR: polymerase chain reaction; RF: rheumatoid factor; TSH: thyroid stimulating hormone; VGCC: anti-voltage gated Ca+ channel; VGKC: anti-voltage gated K+ channel.
Given the diagnostic uncertainty, the patient underwent biopsy of the involved right cerebellum, which identified a lymphocytic infiltrate involving all layers of the cerebellum and extending into the white matter (Figure 2(a)). There was perivascular and meningeal involvement composed predominantly of CD3+ T cells (Figure 2(c)) with only occasional CD20+ B cells (Figure 2(d)). There were numerous CD68+ microglia/macrophages (Figure 2(b)). There were no changes to suggest vasculitis or demyelination. No viral inclusions, atypical lymphoid cells, granulomas or microglial nodules were detected. There was no evidence of monoclonal T, or B, cell disease. These findings are consistent with the diagnostic histopathological criteria for CLIPPERS recently proposed by Tobin and colleagues (1).
Histopathological findings of the right cerebellar biopsy. (a) Haematoxylin and eosin stain showing lymphocytic infiltrate in the cerebellar cortex with extension into the white matter. (b) Staining (brown) for CD68 positive microglia demonstrates activated macrophages/microglia in the molecular layer of the cerebellum which has been reported in CLIPPERS (5). (c) Staining for CD3 positive T cells; and (d) CD20 positive B cells demonstrating an infiltrate of predominantly CD3 positive T lymphocytes, with only occasional B lymphocytes, in the leptomeninges, typical of CLIPPERS (4,5). Scale bars: (a), (c), and (d) = 100 µm, (b) = 200 µm.
The impression was of clinical, neuroimaging and histopathological findings in keeping with CLIPPERS. The patient was treated with intravenous pulse methylprednisolone 1 gram daily for 3 days followed by oral prednisone 60 mg daily, which was gradually weaned over 3 months to a maintenance dose of 2 mg. Her facial pain and paraesthesias improved within weeks. There was a dramatic reduction in the abnormal enhancement (Figures 1(b), (e), (h)), and T2 flair hyperintensity, seen in the cerebellum, pons and spinal cord on MRI 2 weeks post treatment, with complete resolution at 3 months post treatment (Figures 1(c), (f), (i)). The rapid clinical and radiological response to corticosteroids supported the initial impression of CLIPPERS, despite the somewhat unusual clinical presentation. At last follow-up, 4 years after initial presentation, the patient’s facial pain was well controlled apart from occasional, very brief, attacks of neuralgic pain. Neuroimaging remained stable and she was continued indefinitely on a low maintenance dose of prednisone 2 mg.
Discussion
Isolated trigeminal neuropathies
According to the International Classification of Headache Disorders 3rd edition (ICHD-3), the patient’s facial pain should be categorised as a painful cranial neuropathy, or more specifically, a “painful trigeminal neuropathy attributed to other disorder”, rather than as a secondary trigeminal neuralgia (6). This is despite the fact that the patient clearly had neuropathic pain with brief paroxysms of severe pain triggered by cold wind blowing on her face. The presence of this allodynia is consistent with a painful trigeminal neuropathy, as allodynic areas in this condition are typically larger than the punctate trigger zones present in trigeminal neuralgia, as per ICHD-3 (6).
The key differential aetiologies for an isolated sensory trigeminal neuropathy include: Malignant infiltration; lymphoma; neurosarcoidosis; CTDs, such as Sjogren’s syndrome and systemic lupus erythematous; and demyelination, such as MS (7,8). Specifically, in this case, malignant infiltration and lymphoma were excluded based on the absence of malignant cells on biopsy and CSF cytology, and the absence of monoclonal T or B cell populations on biopsy and negative flow cytometry, respectively. Neurosarcoidosis was deemed highly unlikely due to the normal serum angiotensin-converting enzyme level, the normal chest CT, the PET scan localising increased FDG uptake to the brain only, and the absence of granulomas on biopsy. Connective tissue diseases were excluded by negative antibody tests (Table 1) and the lack of associated clinical symptoms required by diagnostic criteria. The patient did not fulfil criteria for MS.
CLIPPERS: A diagnosis of exclusion
This is the first reported case of CLIPPERS presenting with a painful trigeminal neuropathy, notably without any other significant symptoms or signs referable to brainstem or cerebellar pathology. Whilst other cranial nerve palsies have rarely been reported in CLIPPERS, they have typically occurred as part of a constellation of signs and symptoms. However, Simon et al. reported a case of CLIPPERS in a patient presenting with an isolated right facial nerve palsy but who later developed ataxia (4). Until recently, clinical signs such as nystagmus, dysarthria and ataxia have been considered so characteristic of CLIPPERS that it has been proposed that their absence makes an alternate diagnosis more likely (3). However, recently Tobin and colleagues (2017), have suggested that these clinical signs are not necessary criteria for the diagnosis of CLIPPERS (1). Various serum and CSF laboratory investigations were critical in excluding differentials in this case. Interestingly, oligoclonal bands were detected in CSF, but not serum, which has been reported previously in CLIPPERS, compatible with its presumed immune-mediated pathogenesis (8).
The radiological features of this case were consistent with CLIPPERS, with punctate and curvilinear foci of enhancement, visualised predominantly in the brainstem and cerebellum (9), although the asymmetry of the findings is unusual. Although the original description of CLIPPERS (9) emphasized the pontine-centric predominance of the characteristic radiological changes as one of the defining features of the disorder, more recent studies (1,4) have recognized that isolated involvement of the pons, brachium pontis or cerebellum can occur in otherwise typical cases and hence, pontine predominant lesions are no longer considered a sine qua non for the diagnosis of CLIPPERS. Of particular relevance to this case, neuroimaging also identified marked enhancement of the right trigeminal nerve, consistent with the patient’s right-sided facial pain and sensory loss. To the best of the authors’ knowledge, gadolinium enhancement of the trigeminal nerve (or any other cranial nerve) has not previously been reported in CLIPPERS. It is possible that, in this case, the early and prominent involvement of the trigeminal nerve, causing considerable facial pain and sensory changes, may have brought the patient to attention much earlier than might otherwise have happened, and hence before the more typical MRI changes had time to develop. The initial, transient right occipital headache can be explained by the right cervico-medullary lesion.
Whilst previous cases of presumed CLIPPERS have been diagnosed without brain biopsy (10), this non-invasive approach remains controversial. Other studies have detected CNS lymphoma (11), low-grade glioma and primary angiitis of the CNS (12) on histopathology of brain biopsies in patients whose clinical and radiological presentations were otherwise considered suggestive of CLIPPERS. Because of the relatively unusual clinical presentation in this case, correlation between histopathology, neuroimaging and responsiveness to glucocorticosteroid therapy, were critical to diagnosis. Notably, the rapid clinical and radiological responsiveness to glucocorticosteroid treatment, as occurred in this case, appears to be a universal defining feature of CLIPPERS (1,3). Despite complete radiological resolution of the disease, the patient still had mild residual neuropathic pain. This suggests that early diagnosis and treatment of CLIPPERS, particularly when presenting with a painful trigeminal neuropathy, may be imperative in reducing the likelihood of persisting neuralgic pain.
Clinical implications
This report offers a contrary perspective to literature suggesting that cerebellar symptoms/signs are defining clinical features for the diagnosis of CLIPPERS. Considering a broad range of differentials and performing thorough investigation of possible cases of CLIPPERS is critical to early diagnosis and treatment. CLIPPERS should be considered in the list of differentials for an isolated trigeminal neuropathy.
Footnotes
Consent
Informed consent was obtained from the patient to utilise her medical records and case for the purpose of this report. All information has been appropriately de-identified.
Acknowledgements
We thank Dr Max Yan, pathologist, Prince of Wales Hospital, for reviewing and providing the histopathology images.
Declaration of conflicting interests
The authors declared the following potential conflicts of interest with respect to the research, authorship, and/or publication of this article: Alessandro Zagami is an Assistant Editor for Cephalalgia. SamanthaBobba and Manisha Narasimhan have no conflicts to declare.
Funding
The authors received no financial support for the research, authorship, and/or publication of this article.