Hemidysgeusia, phantosmia and respiratory arrest: a case of CLIPPERS

Abstract

A 56-year-old man presented with a relapse of likely chronic lymphocytic inflammation with pontine perivascular enhancement responsive to steroids (CLIPPERS) after a reduction of steroid dose. MRI demonstrated new perivascular FLuid-Attenuated Inversion Recovery (FLAIR) signal hyperintensity involving the dorsal pontomedullary junction and progressing inferiorly into the dorsal medulla oblongata. His admission to hospital was complicated by a respiratory arrest.

Background

Chronic lymphocytic inflammation with pontine perivascular enhancement responsive to steroids (CLIPPERS) is a recently described syndrome¹ consisting of pontine neurological signs and symptoms, with a typical MRI appearance and demonstrated responsiveness to steroids. This case highlights a potentially fatal manifestation of CLIPPERS syndrome due to medullary involvement.

Case presentation

A 56-year-old right-handed man presented to an ophthalmologist in January 2017 with fluctuating diplopia and had an initial working diagnosis of myasthenia gravis. Acetylcholine receptor and muscle-specific kinase (MuSK) antibodies were negative. When referred for neurology review in May 2017, he had internuclear ophthalmoplegia, hemidysgeusia and phantosmia.

There was intermittent diplopia, sometimes perceived as blurred vision worse on lateral gaze. There was no orbital pain or facial sensory disturbance.

There was intermittent awareness of the smell of smoke and perceived altered sense of taste on the left side of his tongue.

Medical history included ischaemic heart disease treated with coronary stenting and hypertension.

On examination he had bilateral internuclear ophthalmoplegia, with no impairment of vertical gaze. Other cranial nerve examination was unremarkable. Formal testing of taste was not performed. There were no long tract signs in the upper and lower limbs.

MRI brain demonstrated T2/FLAIR hyperintensities in the brainstem with perivascular pattern of abnormal enhancement characteristic of CLIPPERS syndrome (see figure 1A).

Figure 1.

Gadolinium-enhanced midline sagittal Turbo Spin Echo (TSE) T1-weighted sequences (B and D) and gadolinium-enhanced Magnetization-Prepared RApid Gradient Echo (MPRAGE) midline sagittal MultiPlanar Reconstructions (MPR) (A and C) showing midbrain involvement 6 weeks after initial presentation and following clinical deterioration (A), 13 weeks after initial presentation showing response following steroid therapy (B), 65 weeks after initial presentation following a clinical deterioration and increasing medullary involvement (C) and 19 months following initial presentation demonstrating near complete radiological resolution of pontomedullary changes following steroid therapy (D).

Further investigations were unremarkable: full blood count, renal function, hepatic function and inflammatory markers were normal. Antibody panel was negative for antinuclear antibody (ANA), extractable nuclear antigen antibodies (ENA), anti-neutrophil cytoplasmic antibody (ANCA), anti-aquaporin 4 (anti -AQP4), cardiolipin IgG and IgM and beta-2 glycoprotein 1 antibody. Cerebrospinal fluid (CSF) examination was acellular, with normal protein, negative oligoclonal bands and negative flow cytometry.

He was diagnosed with CLIPPERS and treated with 3 days of intravenous methylprednisolone 1 g. He was discharged on prednisolone, tapering from 50 mg daily. He noted significant improvement in his symptoms within 2–3 days of commencement of steroids.

He was asymptomatic on 15 mg of prednisolone, with MRI brain on August 2017 demonstrating substantial improvement in multifocal oedematous brainstem lesions, with only residual punctate lesions at the left posterior paramedian dorsal medulla and at the level of the pons at the floor of the fourth ventricle on the right, as well as a few patchy residual hyperintensities at the right middle cerebellar peduncle (see figure 1B). The prednisolone was gradually reduced to 10 mg daily by February 2018 (8 months after initiation of therapy).

In July 2018, he presented to the emergency department with a 1 week history of dysarthria, facial droop, instability of gait and persistent hiccups. The patient had self-increased his prednisolone to 12.5 mg daily 3 months earlier because of perceived worsening fatigue.

On examination he had dysphonia, mild dysarthria and some reduced facial mobility. There was mild midline ataxia.

The initial impression was of exacerbation of his previous CLIPPERS, and outpatient management with increase steroid dose was considered. Fortunately, he was admitted to hospital and urgent MRI brain was arranged.

Investigations

MRI brain performed on day of admission demonstrated new perivascular FLAIR signal hyperintensity, including in the dorsal pontomedullary junction, extending superior to the superior cerebellar peduncles and progression inferiorly into the dorsal medulla oblongata with involvement of the hypoglossal/vagal trigones (see figure 1C).

Treatment

On the evening of day one of admission he had a respiratory arrest on the ward.

Return of spontaneous circulation was achieved after two cycles of resuscitation.

The patient was admitted to intensive care unit for ventilatory support following the arrest.

Immunotherapy was escalated with intravenous methylprednisolone 1 g for 3 days, followed by 50 mg of oral prednisolone.

He was also investigated for cardiac causes of the respiratory arrest, with a satisfactory echocardiogram and myocardial perfusion scan. His ICU admission was complicated by aspiration pneumonia, syndrome of inappropriate anti-diuretic hormone secretion (SIADH) and malaena secondary to severe reflux oesophagitis.

Outcome and follow-up

The patient improved quickly with escalation of steroid therapy. The period on ventilatory support was longer than originally anticipated, attributed to central hypoventilation. In retrospect, he also likely had a prior long period of undiagnosed sleep apnoea. He was extubated on day 5.

Repeat CSF was acellular with negative flow cytometry. CT chest, abdomen and pelvis showed a small emphysematous bulla in the right upper lung and hepatic steatosis. There was no lymphadenopathy. Whole body Positron-Emission Tomography (PET) scan did not demonstrate abnormal fludeoxyglucose (FDG) uptake.

He was discharged on prednisolone 50 mg daily and Continuous Positive Airway Pressure (CPAP).

Sleep study performed after the patient was clinically improved did not demonstrate evidence of a central hypoventilation syndrome.

Four weeks after escalation of therapy, he had minimal dysphonia and fatigue but no other localising signs or symptoms. He remained on CPAP.

Three months following relapse, he was on prednisolone 15 mg. This was considered a reasonable maintenance dose in view of relapse on 10 mg. Methotrexate was commenced as a potential steroid-sparing agent.

Five months after relapse, MRI brain showed near total resolution of abnormal signal (see figure 1D).

Discussion

CLIPPERS is an inflammatory central nervous system disorder first described by Pittock et al,¹ characterised by a combination of brainstem clinical symptoms and characteristic MRI appearance responsive to steroids.

CLIPPERS commonly presents with symptoms related to brainstem involvement such as ataxia, dysarthria, oculomotor abnormalities, tingling of the face and vertigo.² Rarely, CLIPPERS may also present with cortical lesions and seizures as the initial presentation.^{3 4}

Criteria for the diagnosis of CLIPPERS have been recently described by Tobin et al (box 1) and suggest a combination between clinical, imaging and neuropathological findings for a diagnosis.⁵

Box 1. Criteria for the diagnosis of CLIPPERS (from Tobin et al ⁵).

Diagnostic criteria

1. Clinical

   1. Subacute pontocerebellar dysfunction, with or without other Central Nervous System (CNS) symptoms such as cognitive dysfunction and myelopathy.

   2. CNS symptoms responsive to corticosteroid therapy.

   3. Absence of peripheral nervous system disease.

   4. Lack of alternative better explanation for clinical presentation.

2. MRI

   1. Homogenous, gadolinium-enhancing nodules without ring enhancement or mass effect predominating in the pons and cerebellum, measuring <3 mm in diameter.

   2. Marked improvement in abnormal gadolinium enhancement with corticosteroid treatment.

   3. Homogenous T2 signal abnormality where degree of T2 does not significantly exceed the size of the area of post gadolinium enhancement.

   4. Spinal cord lesions with similar T2 and gadolinium enhancing lesions as above.

3. Neuropathology

   1. Dense lymphocytic inflammation with perivascular predominance and parenchymal diffuse infiltration; both white matter and grey matter could be involved.

   2. T cells predominating infiltration (CD4>CD8) with variable macrophage components.

   3. Absence of myelin loss or focal secondary myelin loss.

   4. Lack of alternative better explanation for pathological presentation.

Definite chronic lymphocytic inflammation with pontine perivascular enhancement responsive to steroids (CLIPPERS): patient fulfilling all clinical, radiological criteria and neuropathological criteria.

Probable CLIPPERS: patients fulfilling all clinical and radiological criteria without available neuropathology.

Along with typical responsiveness to steroids, patients with CLIPPERS have also been found to have high rates of clinical relapse following glucocorticoid tapering, requiring maintenance glucocorticoid or other immunosuppressive therapy.⁶

Hemidysgeusia in our case is likely due to involvement of the taste fibres as they ascend in the ipsilateral pons. Although taste was not formally tested, the patient was able to clearly describe unilateral altered taste when eating certain foods. Landis et al ⁷ report the case of a patient with a right-sided pontine stroke from vertebral artery occlusion presenting with vertical diplopia, right-sided deafness, right facial palsy and transient hemiageusia. Their findings strongly suggest that taste fibres have their decussation at a level above the pons and that pontine pathology can cause ipsilateral hemidysgeusia.

The patient’s phantosmia may have been due to temporal lobe epilepsy. Seizures have previously been described in CLIPPERS due to cortical involvement.⁴ This suggests that even though the pontine is the most commonly affected area of the cerebrum, cortical involvement can present atypically. Blaabjerg et al ⁸ have previously investigated inflammation in CLIPPERS through the use of ultra-high field 7.0T MRI and autopsy. They demonstrated perivascular inflammation detected in the brainstem and cerebellum and in brain areas with normal appearance on 3T MRI. In patients with clinical remission, 7.0T MRI revealed supratentorial lesions and perivascular pathology.

Breathing is under the control of three important brainstem respiratory centres: the pontine respiratory group, the dorsal respiratory group and the ventral respiratory group.⁹ Ventral respiratory group neurons are present in the ventrolateral medulla and contain the Bötzinger and pre-Bötzinger complex of neurons, which are now recognised as the respiratory pacemaker.¹⁰ A study conducted by Pattinson et al ¹¹ in 2008 demonstrated activity of the lateral medulla on functional MRI in the setting of simulated respiration with CO₂ stimulation. This is the proposed location of the pre-Bötzinger complex, and MRI of our patient demonstrated involvement of this nucleus (see figures 2 and 3).

Figure 2.

T2 3D driven equilibrium (DRIVE) axial through the medulla oblongata showing hyperintense signal in the regions of the pre-Bötzinger complexes (A), same T2 3D DRIVE axial labelled with the inferior olivary nucleus (ION), pre-Bötzinger complex (PreBötzC), ambigual nucleus (Amb), the inferior cerebellar peduncle (ICP) and the vagus nerve (CN X) (B) and gadolinium-enhanced T1 3D turbo field echo (TFE) spectral presaturation with inversion recovery axial demonstrating foci of enhancement in the regions of the pre-Bötzinger complexes (C).

Figure 3.

T2 Dixon coronal showing hyperintensity in the medulla oblongata in the region of the pre-Bötzinger complex (pre-BötzC) (A), same T2 Dixon coronal labelled with the facial nerve nucleus (CN VII), pre-BötzC) and the lateral reticular nucleus (LRN) (B), gadolinium-enhanced THRIVE (T1-weighted High Resolution Isotropic Volume Examination) coronal demonstrating enhancement in the region of the pre-BötzC (C).

Neurological insult such as stroke, tumour and multiple systems atrophy have been reported to cause respiratory abnormalities and respiratory arrest, and in some studies this has been attributed to degeneration of the nucleus and pre-Bötzinger complex.¹²

This patient with known CLIPPERS involving the medulla illustrates previously unreported risk of respiratory arrest due to involvement of the respiratory centres in the dorsal pontomedullary junction.

Learning points.

• Chronic lymphocytic inflammation with pontine perivascular enhancement responsive to steroids (CLIPPERS) is a recently described syndrome consisting of pontine neurological signs and symptoms, with a typical MRI appearance, and demonstrated responsiveness and dependency on steroids.

• Medullary involvement can present as vomiting, hiccups and taste disturbance and may herald respiratory complications.

• Patients should be carefully monitored for risk of respiratory compromise.