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Meningoencephalitis or meningitis in relapsing polychondritis: Four case reports and a literature review
Journal of Clinical Neuroscience 18 (2011) 1608–1615
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Clinical Study
Meningoencephalitis or meningitis in relapsing polychondritis: Four case reports and a literature review Z.J. Wang a, C.Q. Pu a, Z.J. Wang b, J.T. Zhang a, X.Q. Wang a, S.Y. Yu a, Q. Shi a, J.X. Liu a, X.L. Huang c, C.J. Fu c, A.J. Liu d, X.S. Huang a,⇑ a
Department of Neurology, Chinese PLA General Hospital, 28 Fu Xing Road, Beijing 100853, China Department of Ophthalmology, Chinese PLA General Hospital, Beijing, China Department of Stomatology, Chinese PLA General Hospital, Beijing, China d Department of Pathology, Chinese PLA General Hospital, Beijing, China b c
a r t i c l e
i n f o
Article history: Received 9 November 2010 Accepted 24 April 2011
Keywords: Autoimmune diseases Meningoencephalitis Relapsing polychondritis
a b s t r a c t Relapsing polychondritis (RP) is a rare autoimmune disease that affects cartilage throughout the body, causing episodic and progressive inflammation. Although rare, RP has diverse acute and subacute nervous system complications, which may sometimes precede systemic manifestations. Here, we report four patients with RP who presented with meningoencephalitis or meningitis without infectious aetiology. In addition, we review the literature for this disease with regard to clinical manifestations and treatment options. Ó 2011 Elsevier Ltd. All rights reserved.
1. Introduction Relapsing polychondritis (RP) was first described by Jaksch-Wartenhorst in 1923 and named by Pearson in 1960.1,2 RP is defined as an episodic and inflammatory disease that affects cartilaginous structures including the elastic cartilage of the ear and nose, the hyaline cartilage of the peripheral joints, the fibrocartilage at axial sites and the cartilage of the tracheobronchial tree.3 Neurological abnormalities occur rarely in RP disease: only five patients with RP with nervous system complications have been reported in China. In this study, we present another four patients with RP with meningoencephalitis. We review the literature and provide clinical observations and treatment options.
2. Patients 2.1. Patient 1 A 54-year-old man with a 5-month history of arthralgia and recurrent pain, swelling and erythema in the auricles and eye redness presented with bipolar disorder, fever, headache, dullness, memory loss, and auditory and visual hallucinations. The patient showed memory loss, acalculia, disorientation, neck stiffness, and ⇑ Corresponding author. Tel.: +86 010 88626887; fax: +86 010 66939251. E-mail address: [email protected] (X.S. Huang). 0967-5868/$ - see front matter Ó 2011 Elsevier Ltd. All rights reserved. doi:10.1016/j.jocn.2011.04.012
bilateral Hoffmann signs. Both the patient’s relatives and the doctors had neglected the patient’s symptoms of slight pain and redness in the ears and eyes. Blood tests revealed an elevated white blood cell (WBC) count and C-reactive protein (CRP) concentration and an elevated erythrocyte sedimentation rate (ESR). Cerebrospinal fluid (CSF) studies revealed pleocytosis with a predominance of lymphocytes (Table 1). Brain MRI showed extensive abnormal signal in the white matter on T2-weighted imaging (T2WI). Contrast-enhanced MRI revealed bilateral auricle enhancement (not shown). The patient was suspected to have viral encephalitis and experienced symptomatic relief after being treated with dexamethasone and acyclovir for 20 days. One month later, a flareup of the eye and ear symptoms was associated with a manic episode, insomnia, irritability, restlessness, delusions, and auditory and visual hallucinations. An electroencephalogram demonstrated a background of a-rhythms with a slow wave, indicating a lesion in the frontal and temporal lobes. Audiograms revealed bilateral sensorineural hearing loss. The patient was diagnosed as having RP and was treated with 0.4 g intravenous cyclophosphamide per week and 24 mg oral methylprednisolone per day. Although eye redness and auricular chondritis disappeared after treatment, the psychiatric symptoms worsened. Neurological examination revealed slurred speech, babbling, time and place disorientation, cogwheel rigidity, bilateral brisk tendon reflexes, positive ankle clonus, positive left Chaddock sign and slight neck stiffness. Laboratory data concerned with connective tissue diseases were all negative. A CSF test was normal except for a slightly elevated pro-
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Z.J. Wang et al. / Journal of Clinical Neuroscience 18 (2011) 1608–1615 Table 1 Cerebrospinal fluid profile of patients with relapsing polychondritis Patient
Patient 1
Patient 2
Patient 3
Patient 4
Age (years)/gender
CSF profile (Units) (Normal range) Leucocytes (/mm3) (0–5) (Leucocytes/PMN/mononuclear cells)
Protein (g/L) (0.15–0.45)
Glucose (mmol/L) (2.8–4.5)
Opening P (mmH2O) (80–180)
54/Male 20/03/2009 30/03/2009 19/06/2009
Normal 800/0/800 (lymphocytes95%+monocytes5%) Normal
0.60 0.53 0.51
Normal Normal Normal
230 190 normal
44/Male 04/08/2009 18/08/2009 01/09/2009 08/09/2009
190/17/171 96/16/80 Normal 12*
0.57 0.67 Normal Normal
Normal Normal Normal Normal
Normal Normal Normal Normal
52/Male 07/11/2009 23//11/2009 04/12/2009 21/12/2009 06/01/2010 30/01/2010 27/05/2010
230/161/69 43/4/39 18* 105/58/47 18* Normal No details
0.51 0.70 1.01 0.46 Normal Normal No details
1.5 2.0 1.9 2.1 2.1 Normal No details
195 300 >300 >300 300 205 280
44/Female 02/02/2010 24/02/2010
70/28/42 Normal
0.71 Normal
2.4 2.3
Normal Normal
CSF = cerebrospinal fluid, Opening P = opening pressure, PMN = polymorphonuclear leucocytes. No record of cellular fraction.
*
tein level (Table 1). The CSF and serum were evaluated for neoplasm and infectious pathogens, including herpes simplex virus (HSV), with negative findings. MRI revealed more extensive abnormal signal in the white matter (Fig. 1A). A biopsy of the auricular cartilage revealed an infiltration of chronic inflammatory cells into the cartilaginous and perichondrial tissues (Fig. 2A). These results enabled us to establish a diagnosis of meningoencephalitis with RP. The patient received a daily dose of 1000 mg of intravenous methylprednisolone for 3 days, which was then decreased to 80 mg per day, and oral azathioprine, 100 mg per day; olanzapine and chloral hydrate were administered for psychiatric symptoms. The psychiatric symptoms improved slowly, and arthralgia, auricular chondritis and ocular inflammation did not recur. Five months later, brain MRI showed that the lesions had decreased and the ventricles were enlarged (Fig. 1B). At the last examination, the patient was taking prednisone and azathioprine and appeared well.
2.2. Patient 2 A 44-year-old man presented with amnesia for 20 days and arthralgia for 30 days. Brain MRI revealed hyperintense lesions in the left hippocampus on T2WI (Fig. 1C). On admission, a neurological examination revealed amnesia and positive right Kernig’s sign. CSF tests revealed mononuclear pleocytosis with mildly elevated protein levels (Table 1). Viral encephalitis was suspected, and acyclovir was administered. During the patient’s hospitalisation, ocular inflammation and auricular chondritis occurred twice (Fig. 3A–C). The patient became irritated and anxious. A blood test showed elevated levels of WBC, CRP, ESR, complement 3, 4 and immunoglobulin E. Laboratory data associated with connective tissue diseases were within the normal range. The CSF and serum were evaluated for neoplasm and infectious agents, including herpes simplex virus (HSV), with negative findings. Brain MRI showed lesions involving the white matter in the right periventricular area and the right temporal lobe (Fig. 1D and E). Abnormal signal was also detected in the bilateral auricles (Fig. 1F and G). An auricular cartilage biopsy revealed the infiltration of acute inflammatory
cells and cartilage degeneration (Fig. 2B). The patient was diagnosed as having encephalitis with RP and was treated with intravenous methylprednisolone, 200 mg daily for 5 days, followed by 120 mg daily. One week later, the symptoms of ocular inflammation and cauliflower ear disappeared (Fig. 3D–F), and the patient felt well. The patient was then administered a daily oral dose of 60 mg of prednisone and 100 mg of azathioprine. MRI performed 3 months after discharge revealed improved results. During a 6month follow-up, the patient remained well without neurologic disorders while continuing to receive prednisone, 25 mg per day, and azathioprine, 100 mg per day, orally.
2.3. Patient 3 A 52-year-old man with mental changes for 1 year and a lowgrade fever for 15 days presented with arthralgia, eye redness, headache, memory loss, difficulty in communicating, deafness, gait disorders and urinary incontinence. On admission, physical examination showed eye redness (Fig. 4A), hypertrophic tough auricles (Fig. 4B), memory loss, difficulty in communicating and understanding, slow responsiveness, acalculia, papilledema (Fig. 4D and E), cogwheel phenomenon and tremor in both upper extremities with slight hypertonia and a stiff neck. The Mini-Mental State Examination score was 17/30. A blood test revealed leukocytosis with elevated ESR and CRP levels. Laboratory data associated with connective tissue diseases were all negative. CSF tests revealed polymorphonuclear (PMN) and mononuclear pleocytosis with high intracranial pressure, low levels of glucose content and high levels of protein (Table 1). The CSF and serum were also evaluated for neoplasm and infectious agents, including tuberculosis (TB), and herpes simplex virus (HSV), with negative findings. Review of brain MRI and CT scans from the previous year indicated worsening ventricular enlargement (Fig. 1H–J) and abnormal signals in the bilateral auricles (Fig. 1K). Tuberculous meningitis was initially suspected, and 5 mg of intravenous dexamethasone per day was administered. Eye redness recurred with discontinued or decreased dexamethasone treatment. After 5 weeks of antituberculous
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Fig. 1. Axial MRI and CT scans of Patients 1, 2, 3, and 4. (A, B) Patient 1. (A) T2-weighted MRI (T2WI) showing lesions involving the white matter in the periventricular area (arrows), and homogeneous hyperintensity; and (B) with treatment, the lesion areas decreased (arrow), and the lateral ventricles enlarged (arrow). (C–G) Patient 2. (C) T2WI showing hyperintense lesions in the left hippocampus (arrow), and (D) coronal fluid-attenuated inversion recovery (FLAIR) and (E) T2WI showing homogeneous hyperintensity (arrows) and lesions involving the white matter in the right periventricular area (arrow) and the right temporal lobe (arrow); (F) diffusion weighted image (DWI) showing abnormal signal in the bilateral auricles (arrow), and (G) post contrast T1-weighted MRI (T1WI) showing enhancement of the bilateral auricles (arrows). (H–K) Patient 3. (H) T1WI MRI showing no abnormal signal; (I, J) Imaging 15 days before admission showing (I) CT scan showing enlarged lateral ventricles (arrow) and third ventricle; and (J) T1WI showing more obvious enlargement of the lateral ventricles (arrow); (K) DWI showing an abnormal signal in the bilateral auricles (arrow). (L–N) Patient 4. (L) CT scan (M) T2WI and (N) DWI showing normal scans except for an abnormal signal in the left auricle (arrow).
therapy, no effects were detected, and the diagnosis was questioned. An auricle biopsy demonstrated hyperplasia and chondrocyte derangement (Fig. 2C). In combination with the chronic auricular chondritis, ocular inflammation, arthralgia and histological findings, hydrocephalus arising from aseptic meningitis related to RP was diagnosed. Intravenous methylprednisolone, 500 mg daily, and intravenous human immunoglobulin, 30 g daily, were administered over 5 consecutive days; antituberculous therapy was discontinued. The patient’s neurological symptoms improved
considerably with the disappearance of conjunctivitis (Fig. 4C), softened auricles and the disappearance of arthralgia. On discharge, the patient’s condition was good, and a CSF study was normal except for slightly high opening pressure (Table 1). When 3 months later oral prednisolone was decreased to 20 mg per day, relatives of the patient reported that conjunctivitis and slow responsiveness recurred. A CSF study showed an opening pressure of 280 mmH2O without more available details concerning pleocytosis and protein level. The symptoms improved considerably after steroid pulse therapy.
Z.J. Wang et al. / Journal of Clinical Neuroscience 18 (2011) 1608–1615
Fig. 2. Biopsies of ear cartilage showing loss of basophilic staining in the cartilage matrix: (A) Patient 1 – infiltration of chronic inflammatory cells into cartilaginous and perichondrial tissues (hematoxylin and eosin [HE] stain; (B) Patient 2 – infiltration of acute inflammatory cells and degeneration of cartilage (HE stain); (C) Patient 3 – hyperplasia and derangement of chondrocytes (HE stain) and (D) inflammation of cartilage and surrounding tissues (HE stain). Scale bar represents 50 lm.
2.4. Patient 4 A 44-year-old woman with pain in the sternoclavicular, neck, back and sacroiliac joints, anorexia, fatigue, anxiety, insomnia and weight loss for 1 year presented with left ear pain and swelling and hoarseness for 1 week. No headache was reported. Physical examination revealed left auricle swelling, redness (Fig. 4F) and tenderness, neck stiffness, Brudzinski signs and bilateral Kernig’s sign. A bone marrow puncture revealed bone marrow inflammation and hyperplasia of megakaryocytes. Blood tests revealed leukocytosis with anemia, thrombocytosis, and elevated ESR and CRP level. Laboratory data associated with connective tissue diseases were all within the normal range, except that the antinuclear antibodies (1:160) showed a speckled pattern. The CA 125 level was 267.8 l/mL (0.1–35 l/mL). Hypolipemia and hypoproteinemia were also observed. A CSF study showed mild mononuclear pleocytosis with mildly elevated levels of protein, a mildly
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decreased glucose content and normal opening pressure (Table 1). The CSF and serum were evaluated for neoplasm and infectious agents, including herpes simplex virus (HSV), TB, and Cryptococcus neoformans, with negative findings. The results of a laryngoscopy were normal. CT scans and brain MRI were both normal except for abnormal signal in the left auricle (Fig. 1L–N). Position emission tomography revealed slight hypermetabolism in the left ear and skeleton of the trunk but no hypermetabolism indicating a neoplasm. In combination with the auricular chondritis, and inflammation of peripheral joints and the fibrocartilage at axial sites and the larynx, cerebrospinal meningitis with RP was suspected. Intravenous methylprednisolone at a dose of 500 mg daily was administered, and the patient’s symptoms improved considerably. A flare-up in the left ear recurred when methylprednisolone was decreased to 120 mg per day. Consequently, methylprednisolone was decreased at a slower rate, and oral azothioprine was prescribed at a dose of 100 mg per day. Cauliflower ear also disappeared (Fig. 4G). After steroid therapy, a biopsy of the left ear still showed inflammation of the cartilage and surrounding tissues (Fig. 2D). On discharge, the results of the blood and CSF tests were almost normal, except that the CA 125 level was only reduced to 58.17 l/mL. The patient’s condition was good, and the symptoms had not recurred at the 3-month follow-up.
3. Discussion RP is a rare disorder characterised by recurrent episodes of inflammation of cartilaginous tissue. Any type of cartilage can be involved in RP, including auricular, nasal, tracheobronchial, valvular, and articular cartilage. RP can also involve other proteoglycanrich structures, such as the eyes, heart, blood vessels, inner ears and kidneys. The aetiology of RP is unknown. Type II collagen is most commonly involved.4 Both humoural and cellular immunity are thought to be involved. Most cases of RP are diagnosed in the fifth decade of life; the mean delay in diagnosis is 2.9 years. There is no gender difference. The diagnosis of RP is based primarily on clinical features. According to the criteria proposed by McAdam et al.,3 a diagnosis of RP can be established if three or more of the six clinical features (auricular chondritis, nonerosive inflammatory polyarthritis, nasal chondritis, ocular inflammation, respiratory tract chondritis or audiovestibular damage) are present along with positive histological findings. RP diagnosis can also be established if one or more of McAdam’s signs with positive histological confirmation are present or two or more separate anatomical locations are involved, along with a response to
Fig. 3. Patient 2. Photographs showing: (A) marked auricular swelling and redness; (B) bilateral conjunctivitis; (C) slit lamp image of conjunctivitis; (D–F) ear, eye, and slit lamp examination after steroid pulse therapy showing that the symptoms of ocular inflammation and cauliflower ear had disappeared.
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steroids and/or dapsone (diamino-diphenyl sulfone). This expanded criteria was proposed by Damiani and Levine; 5 according to them, histological examination of affected cartilage shows a loss of basophilic staining in the cartilage matrix, perichondrial
inflammation, and cartilage destruction with replacement by fibrous tissue. There is also lacunar breakdown and infiltration of neutrophils. As inflammation continues, there is condensation into irregular whorls of collagen with plasma cell and lymphocytic
Fig. 4. Patients 3 and 4. Patient 3 – photographs of symptoms and the fundus showing: (A) eye redness, (B) hypertrophic tough auricles, (C) the disappearance of eye redness and conjunctivitis, and (D, E) the fundus showing papilledema. Patient 4 – symptoms showing (F) left auricle swelling and redness (cauliflower ear), and (G) reduced auricular swelling on the left after treatment.
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infiltration. Chondrocytes dedifferentiate, forming fibroblasts and collagen fibres. Occasionally, small sites of cartilage regenerate. There is a loss of matrix acid mucopolysaccharides. The patients described in this study presented with auricular chondritis (Patients 1, 2, 3, and 4), ocular inflammation (Patients 1, 2, and 3), nonerosive inflammatory polyarthritis (Patients 1, 2, 3, and 4), laryngeal involvement (Patient 4), audiovestibular damage (Patient 1), and positive histological findings and their responses to steroids (Patients 1, 2, 3, and 4); these symptoms met the criteria proposed by both McAdam et al. and Damiani and Levine. Frostbite and infectious chondritis were excluded before the diagnosis of RP was made in our patients. We also excluded systemic lupus erythematosus, rheumatoid arthritis, Wegener’s granulomatosis, systemic sclerosis and paraneoplastic syndrome based on the clinical presentation and laboratory examinations. A few previous patients have been reported with meningoencephalitis with RP. A detailed search of all of the relevant English
language literature published between 1960 and 2010 via PubMed (http://www.ncbi.nlm.nih.gov/pubmed) was performed, using ‘‘relapsing polychondritis’’ and ‘‘nervous system’’ as keywords. Meningoencephalitis in patients with RP was found in 24 previous reports. The details of the 28 patients, including our four patients, are summarised in Table 2.6–26 Patient 1 had extensive white matter lesions that led to a psychiatric disorder and memory loss. Patient 2 first had a lesion in the left hippocampus, which led to amnesia; the mood disorder might have arisen from the temporal lobe lesion. The clinical manifestation was limbic encephalitis. The syndromes seen in Patient 3 could have been the result of raised intracranial pressure due to hydrocephalus arising from aseptic meningitis related to RP. The clinical manifestation in Patient 4 was aseptic cerebrospinal meningitis. The male-to-female ratio in the 28 patients was 19:9. The age of onset of meningoencephalitis related to RP was between 30 and 73 years. The average age of patients was 56 years. Including our four patients, 13 were
Table 2 Reports of patients with relapsing polychondritis and meningoencephalitis YearRef
Age/sex
Associated neurologic disorders (most cases had fever, headache or meningeal irritation signs)
Brain pathology
Response to steroid
Recurrent meningitis
19886
52/M
Generalized tonic-clonic seizure, impaired cognitive function, impaired visual acuity, hearing loss
Yes
Yes
Yes
19887
30/F 75/M 62/F
Hearing loss, unsteadiness Hearing loss, personality changes Hearing loss
No Yes No
Not used Yes Unknown
No No No
19928
73/F
Right ptosis, unilateral facial weakness, hearing loss
No
Yes
No
19949
70/F
Confusion, memory loss, unstable gait
No
Yes
No
199510
36/M
Diplopia, tinnitus, papilledema
No
Yes
No
199611
60/M
Ataxia, hearing loss, hydrocephalus
Yes
Yes
Yes
199612
70/M
Hearing loss, disturbances of consciousness
No
Yes
Yes
199813
66/M
Focal seizure
Yes
Yes
No
200414
57/M
Nystagmus, hearing loss, papilledema, memory loss
No
Yes
No
200415
49/M
Unsteady gait, somnolence, disorientation
No
Yes
No
200416
45/M
Disorientation, euphoria, confabulation, memory impairment Memory impairment, confusion, euphoria*
Yes
Yes
No
No
Yes
No
200517
57/F
Deafness, general convulsion, delirium, personality change
No
Yes
Yes
200618
53/M
Memory loss, cognitive impairment, aggressive and abusive behavior*
Yes
No
Yes
62/M
200619
71/F
Confusion, cerebral infarction
No
Yes
200720
40/M
Confusion
No
Yes
Unknown
200821
61/M
Loss of consciousness, convulsions, slurred speech, hallucination
No
Not used
Unknown
200822
66/F
Sleep inversion, tremor, urinary incontinence, gait disorder, memory disturbance, disorientation, akinetic mutism
No
Yes
No
200823
51/M
Coordination problems, distraction, word finding difficulty, emotional lability, jerking, confusion*
Yes
No
Die
200924
62/M
Generalized tonic-clonic convulsion, focal seizure
No
Yes
Yes
200925
56/F
Diplopia
No
Yes
No
201026
63/M
No
Yes
No
Current patients
54/M
No
Yes
Yes
No No
Yes Yes
Yes Yes
No
Yes
No
44/M 52/M
44/F *
Emotional disturbance, acoustic and visual hallucination, memory loss Memory loss, irritability, anxiety Anxiety, insomnia, memory loss, deafness, gait change, urinary incontinence, expressive and receptive aphasia, dullness, acalculia, and papilledema Anxiety, insomnia
No details regarding the presence of fever, headache and meningeal irritation signs were available.
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Caucasian and 15 were Mongolian. Thirteen patients suffered from meningoencephalitis during RP, meningoencephalitis and RP occurred simultaneously in six patients, and nine patients (including our Patients 1, 2, and 3) had an episode of meningoencephalitis before the diagnosis of RP. Early establishment of a diagnosis of meningoencephalitis with RP in this last group was a challenge for neurologists. At onset, most patients in this group had atypical manifestations of RP including dizziness, arthralgia, fever, weight loss and fatigue. When they developed meningoencephalitis, typical signs of RP were not reported or were neglected by doctors (such as occured in Patient 3). In this group, the interval between the onset of meningoencephalitis and the onset of the typical RP signs was from one day to fifteen months. In all cases, patients had clinical manifestations of fever, headache and signs of meningeal irritation. Associated neurological disorders included impaired cognitive function, memory loss, disorientation, expressive and receptive aphasia, dullness, acalculia, personality changes, euphoria, confabulation, hallucination, aggressive and abusive behaviour, disturbances of consciousness, confusion, somnolence, delirium, akinetic mutism, sleep inversion, insomnia, generalised tonic-clonic seizure, focal seizure, unstable gait, impaired visual acuity, papilledema, ptosis, diplopia, unilateral facial weakness, hearing loss, tinnitus, nystagmus, hemiplegia, and urinary incontinence (Table 2). CSF tests revealed pleocytosis in 26 patients, and two patients18,22 had no results. Seventeen patients, including our Patients 1, 2 and 4, showed pleocytosis with a predominance of mononuclear cells, including lymphocytes and monocytes in the CSF.6,7,9,10,14–16,19,21,23,24,26 Six patients showed pleocytosis with a predominance of PMN in the CSF.7,8,12,13,20,25 At first onset of meningoencephalitis, two patients showed pleocytosis with a predominance of mononuclear cells in the CSF, but the recurrences had a predominance of PMN 11,17 Our Patient 3 showed pleocytosis with a predominance of PMN in the CSF at first but later a predominance of mononuclear cells (Table 1). A predominance of PMN was observed in cases with more marked peripheral inflammation. This probably reflected the metabolic consequences of the peripheral manifestations of RP. Some patients presenting with limbic encephalitis or dementia showed lesions in the temporal lobes on MRI.14–16,18,20,23,24 Massry et al.10 reported that MRI in RP may be characterized by bilateral hypertensities in the basal ganglia. Addition of gadolinium enhanced smaller adjacent areas, an area in the left posterior thalamus, and a wedge-shaped area in the cortical grey matter. Three patients have been reported with leptomeningeal enhancement on contrast-enhanced T1-weighted MRI (T1WI).11,13,17 A patient with encephalitis lethargica with RP showed diffuse hyperintense lesions bilaterally in the basal ganglia on T2WI and fluid attenuated inversion recovery (FLAIR) images.22 All of our patients had abnormal signals in the affected auricle on MRI and CT scans, which is similar to the ‘‘prominent ear sign’’ described by Kuwabara et al.21 A biopsy or autopsy of the brain was performed in seven of the 24 previously reported patients summarised in Table 3.6,7,11,13,16,18,23 The aetiology of central nervous system
(CNS) involvement in RP patients is still unknown but seems to originate from autoimmunity. Antibodies to type II collagen have been found in some RP patients. Thus, Brod et al. speculated that remnants of the notochord could serve as antigens in the CNS. They also speculated that an antigen distinct from collagen could be involved in the CNS and that vasculitis could be the cause of neurological disorders in some patients with RP.8 Stewart et al. described diffuse vasculitis of the brain.6 Massry et al. suggested that cerebral arteritis was associated with RP after analysing the brain MRI of a patient with RP.11 Ragnaud et al. reported that, in a patient suffering from generalised maculopapular eruptions, a biopsy revealed cutaneous vasculitis.12 These studies showed a strong relationship between vasculitis and neurological disorders in some patients with RP. Kashihara et al. found that autoantibodies to the GluRe2 (NR2B) subunit could be associated with limbic encephalitis in certain patients with RP.24 Our four patients declined to undergo a brain biopsy. We speculate that vasculitis or non-specific inflammation may have involved the leptomeninges and the parenchyma of the brain in our four patients. A standardised therapeutic protocol for RP has not been established because of its rarity, the diversity of presentations, the unpredictable recurrence rate and course, and the potential CNS involvement. Corticosteroids are the predominant treatment of choice but cannot stop the progression of the disease or vital organ involvement. Life-threatening complications can occur after repeated relapses and severe ocular involvement. In such instances, immunosuppressive therapy along with systemic steroids and cytotoxic agents are required. Of the 28 reported meningoencephalitis patients with RP, 23 responded to steroid therapy, two did not respond to steroid therapy, and nine displayed recurrent meningitis (Table 2). Systemic steroids were administered to our four patients. Because of the delay in diagnosis, Patient 1 received systemic steroid treatment after two relapses involving the cerebral parenchyma. The clinical manifestations and lesions observed on MRI improved slowly. Patient 2 received systemic steroids early and had no irreversible lesions in the cerebral parenchyma. Although he was disturbed by eye inflammation after hospital discharge, there were no severe sequelae of the CNS. Patient 3 had no obvious lesions in the cerebral parenchyma, and his manifestations arose from raised intracranial pressure due to hydrocephalus. Although the diagnosis was delayed by 1 year, the manifestations improved considerably after systemic steroid therapy. Patient 4 had a long period of atypical RP manifestations without CNS involvement. When aseptic meningitis was diagnosed, steroids were immediately administered and recovery was quick and complete. Concerning systemic steroid therapy, intravenous methylprednisolone should be administered at a dose of 500 to 1000 mg per day for 3 to 5 days and then decreased to a dose of 125 mg per day, followed by oral prednisone at 60 mg per day for 4 weeks (which should then be decreased at a rate of 10 mg every 2 weeks). The administration of cytotoxic agents such as azathioprine may help to reduce the steroid dosage required. Systemic steroids were administered to our four patients, and 100 mg daily of oral azathi-
Table 3 Brain biopsy or autopsy results in patients with relapsing polychondritis and meningitis YearRef
Pathological description
19886 19887 199611 199813 200416
Diffuse vasculitis of the brain Lymphocytic infiltration in the meninges Inflammatory cells without evidence of granulomas; fungal, bacterial and mycobacterial stains and cultures were negative No evidence of vasculitis, although inflammatory changes in the meninges and the cerebral parenchyma were noted Inflammatory cell components consistent with meningoencephalitis which were predominantly T cells, and the histopathological features were not specific for vasculitis Neuronal loss, gliosis and microgial nodules in the hippocampus, cingulate gyrus, temporal and occipital lobes, patchy perivascular cuffing, and leptomeningeal lymphocytic infiltrates in the cerebral cortex, striatum, thalamus and medulla Non-specific inflammation without evidence of vasculitis
200618 200823
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oprine was administered to Patients 1, 2 and 4. The length of treatment depends on the clinical manifestations. 4. Conclusion Meningoencephalitis with RP is a rare condition. The diagnosis is challenging because of its rarity and the diversity of clinical presentations. Our presented patients and literature review emphasise the need for early diagnosis and initiation of immunosuppressive treatment. If specific treatment is delayed, severe sequelae may result during flare-ups of RP. The aetiology of meningoencephalitis associated with RP merits further investigation. References 1. Jaksch-Wartenhorst R. Polychondropathia. Wien Arch Intern Med 1923;6:93–100. 2. Pearson CM, Klene HM, Newcomer VD. Relapsing polychondritis. N Engl J Med 1960;263:51. 3. McAdam LP, O’Hanlan MA, Bluestone R, et al. Relapsing polychondritis: prospective study of 23 patients and a review of the literature. Medicine 1976;55:193–215. 4. Foidart JM, Abe S, Martin GR, et al. Antibodies to type II collagen in relapsing polychondritis. N Engl J Med 1978;299:1203–7. 5. Damiani JM, Levine HL. Relapsing polychondritis – report of ten cases. Laryngoscope 1979;89:929–46. 6. Stewart SS, Ashizawa T, Dudley AW, et al. Cerebral vasculitis in relapsing polychondritis. Neurology 1988;38:150–2. 7. Brod S, Booss J. Idiopathic CSF pleocytosis in relapsing polychondritis. Neurology 1988;38:322–3. 8. Wasserfallen JB, Schaller MD. Unusual rhombencephalitis in relapsing polychondritis. Ann Rheum Dis 1992;51:1184. 9. Hanslik T, Wechsler B, Piette JC, et al. Central nervous system involvement in relapsing polychondritis. Clin Exp Rheumatol 1994;12:539–41. 10. Massry GG, Chung SM, Selhorst JB. Optic neuropathy, headache, and diplopia with MRI suggestive of cerebral arteritis in relapsing polychondritis. J Neuroophthalmol 1995;15:171–5.
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11. Berg AM, Kasznica J, Hopkins P, et al. Relapsing polychondritis and aseptic meningitis. J Rheumatol 1996;23:567–9. 12. Ragnaud JM, Tahbaz A, Morlat P, et al. Recurrent aseptic purulent meningitis in a patient with relapsing polychondritis. Clin Infect Dis 1996;22:374–5. 13. Kothare SV, Chu CC, VanLandingham K, et al. Migratory leptomeningeal inflammation with relapsing polychondritis. Neurology 1998;51:614–7. 14. Ohta Y, Nagano I, Niiya D, et al. Nonparaneoplastic limbic encephalitis with relapsing polychondritis. J Neurol Sci 2004;220:85–8. 15. Yang SM, Chou CT. Relapsing polychondritis with encephalitis. J Clin Rheumatol 2004;10:83–5. 16. Fujiki F, Tsuboi Y, Hashimoto K, et al. Non-herpetic limbic encephalitis associated with relapsing polychondritis. J Neurol Neurosurg Psychiatry 2004;75:1646–7. 17. Ota M, Mizukami K, Hayashi T, et al. Brain magnetic resonance imaging and single photon emission computerized tomography findings in a case of relapsing polychondritis showing cognitive impairment and personality changes. Prog Neuropsychopharmacol Biol Psychiatry 2005;29:347–9. 18. Yan M, Cooper W, Harper C, et al. Dementia in a patient with nonparaneoplastic limbic encephalitis associated with relapsing polychondritis. Pathology 2006;38:596–9. 19. Hsu KC, Wu YR, Lyu RK, et al. Aseptic meningitis and ischemic stroke in relapsing polychondritis. Clin Rheumatol 2006;25:265–7. 20. Kao KT, Potrebic S, Evans JR. Relapsing polychondritis presenting as meningoencephalitis with valvular abnormality: a case report. Clin Rheumatol 2007;26:1985–8. 21. Kuwabara M, Shimono T, Toyomasu M, et al. ‘‘Prominent ear sign’’ on diffusionweighted magnetic resonance imaging in relapsing polychondritis. Radiat Med 2008;26:438–41. 22. Fujioka S, Tsuboi Y, Mikasa M, et al. A case of encephalitis lethargica associated with relapsing polychondritis. Mov Disord 2008;23:2421–3. 23. Erten-Lyons D, Oken B, Woltjer RL, et al. Relapsing polychondritis: an uncommon cause of dementia. J Neurol Neurosurg Psychiatry 2008;79:609–10. 24. Kashihara K, Kawada S, Takahashi Y. Autoantibodies to glutamate receptor GluRepsilon2 in a patient with limbic encephalitis associated with relapsing polychondritis. J Neurol Sci 2009;287:275–7. 25. Yaguchi H, Tsuzaka K, Niino M, et al. Aseptic meningitis with relapsing polychondritis mimicking bacterial meningitis. Intern Med 2009;48:1841–4. 26. Kawai H, Nakajima A. Images in clinical medicine. Red puffy ears. N Engl J Med 2010;362:928.
Contents lists available at ScienceDirect
Journal of Clinical Neuroscience journal homepage: www.elsevier.com/locate/jocn
Clinical Study
Meningoencephalitis or meningitis in relapsing polychondritis: Four case reports and a literature review Z.J. Wang a, C.Q. Pu a, Z.J. Wang b, J.T. Zhang a, X.Q. Wang a, S.Y. Yu a, Q. Shi a, J.X. Liu a, X.L. Huang c, C.J. Fu c, A.J. Liu d, X.S. Huang a,⇑ a
Department of Neurology, Chinese PLA General Hospital, 28 Fu Xing Road, Beijing 100853, China Department of Ophthalmology, Chinese PLA General Hospital, Beijing, China Department of Stomatology, Chinese PLA General Hospital, Beijing, China d Department of Pathology, Chinese PLA General Hospital, Beijing, China b c
a r t i c l e
i n f o
Article history: Received 9 November 2010 Accepted 24 April 2011
Keywords: Autoimmune diseases Meningoencephalitis Relapsing polychondritis
a b s t r a c t Relapsing polychondritis (RP) is a rare autoimmune disease that affects cartilage throughout the body, causing episodic and progressive inflammation. Although rare, RP has diverse acute and subacute nervous system complications, which may sometimes precede systemic manifestations. Here, we report four patients with RP who presented with meningoencephalitis or meningitis without infectious aetiology. In addition, we review the literature for this disease with regard to clinical manifestations and treatment options. Ó 2011 Elsevier Ltd. All rights reserved.
1. Introduction Relapsing polychondritis (RP) was first described by Jaksch-Wartenhorst in 1923 and named by Pearson in 1960.1,2 RP is defined as an episodic and inflammatory disease that affects cartilaginous structures including the elastic cartilage of the ear and nose, the hyaline cartilage of the peripheral joints, the fibrocartilage at axial sites and the cartilage of the tracheobronchial tree.3 Neurological abnormalities occur rarely in RP disease: only five patients with RP with nervous system complications have been reported in China. In this study, we present another four patients with RP with meningoencephalitis. We review the literature and provide clinical observations and treatment options.
2. Patients 2.1. Patient 1 A 54-year-old man with a 5-month history of arthralgia and recurrent pain, swelling and erythema in the auricles and eye redness presented with bipolar disorder, fever, headache, dullness, memory loss, and auditory and visual hallucinations. The patient showed memory loss, acalculia, disorientation, neck stiffness, and ⇑ Corresponding author. Tel.: +86 010 88626887; fax: +86 010 66939251. E-mail address: [email protected] (X.S. Huang). 0967-5868/$ - see front matter Ó 2011 Elsevier Ltd. All rights reserved. doi:10.1016/j.jocn.2011.04.012
bilateral Hoffmann signs. Both the patient’s relatives and the doctors had neglected the patient’s symptoms of slight pain and redness in the ears and eyes. Blood tests revealed an elevated white blood cell (WBC) count and C-reactive protein (CRP) concentration and an elevated erythrocyte sedimentation rate (ESR). Cerebrospinal fluid (CSF) studies revealed pleocytosis with a predominance of lymphocytes (Table 1). Brain MRI showed extensive abnormal signal in the white matter on T2-weighted imaging (T2WI). Contrast-enhanced MRI revealed bilateral auricle enhancement (not shown). The patient was suspected to have viral encephalitis and experienced symptomatic relief after being treated with dexamethasone and acyclovir for 20 days. One month later, a flareup of the eye and ear symptoms was associated with a manic episode, insomnia, irritability, restlessness, delusions, and auditory and visual hallucinations. An electroencephalogram demonstrated a background of a-rhythms with a slow wave, indicating a lesion in the frontal and temporal lobes. Audiograms revealed bilateral sensorineural hearing loss. The patient was diagnosed as having RP and was treated with 0.4 g intravenous cyclophosphamide per week and 24 mg oral methylprednisolone per day. Although eye redness and auricular chondritis disappeared after treatment, the psychiatric symptoms worsened. Neurological examination revealed slurred speech, babbling, time and place disorientation, cogwheel rigidity, bilateral brisk tendon reflexes, positive ankle clonus, positive left Chaddock sign and slight neck stiffness. Laboratory data concerned with connective tissue diseases were all negative. A CSF test was normal except for a slightly elevated pro-
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Z.J. Wang et al. / Journal of Clinical Neuroscience 18 (2011) 1608–1615 Table 1 Cerebrospinal fluid profile of patients with relapsing polychondritis Patient
Patient 1
Patient 2
Patient 3
Patient 4
Age (years)/gender
CSF profile (Units) (Normal range) Leucocytes (/mm3) (0–5) (Leucocytes/PMN/mononuclear cells)
Protein (g/L) (0.15–0.45)
Glucose (mmol/L) (2.8–4.5)
Opening P (mmH2O) (80–180)
54/Male 20/03/2009 30/03/2009 19/06/2009
Normal 800/0/800 (lymphocytes95%+monocytes5%) Normal
0.60 0.53 0.51
Normal Normal Normal
230 190 normal
44/Male 04/08/2009 18/08/2009 01/09/2009 08/09/2009
190/17/171 96/16/80 Normal 12*
0.57 0.67 Normal Normal
Normal Normal Normal Normal
Normal Normal Normal Normal
52/Male 07/11/2009 23//11/2009 04/12/2009 21/12/2009 06/01/2010 30/01/2010 27/05/2010
230/161/69 43/4/39 18* 105/58/47 18* Normal No details
0.51 0.70 1.01 0.46 Normal Normal No details
1.5 2.0 1.9 2.1 2.1 Normal No details
195 300 >300 >300 300 205 280
44/Female 02/02/2010 24/02/2010
70/28/42 Normal
0.71 Normal
2.4 2.3
Normal Normal
CSF = cerebrospinal fluid, Opening P = opening pressure, PMN = polymorphonuclear leucocytes. No record of cellular fraction.
*
tein level (Table 1). The CSF and serum were evaluated for neoplasm and infectious pathogens, including herpes simplex virus (HSV), with negative findings. MRI revealed more extensive abnormal signal in the white matter (Fig. 1A). A biopsy of the auricular cartilage revealed an infiltration of chronic inflammatory cells into the cartilaginous and perichondrial tissues (Fig. 2A). These results enabled us to establish a diagnosis of meningoencephalitis with RP. The patient received a daily dose of 1000 mg of intravenous methylprednisolone for 3 days, which was then decreased to 80 mg per day, and oral azathioprine, 100 mg per day; olanzapine and chloral hydrate were administered for psychiatric symptoms. The psychiatric symptoms improved slowly, and arthralgia, auricular chondritis and ocular inflammation did not recur. Five months later, brain MRI showed that the lesions had decreased and the ventricles were enlarged (Fig. 1B). At the last examination, the patient was taking prednisone and azathioprine and appeared well.
2.2. Patient 2 A 44-year-old man presented with amnesia for 20 days and arthralgia for 30 days. Brain MRI revealed hyperintense lesions in the left hippocampus on T2WI (Fig. 1C). On admission, a neurological examination revealed amnesia and positive right Kernig’s sign. CSF tests revealed mononuclear pleocytosis with mildly elevated protein levels (Table 1). Viral encephalitis was suspected, and acyclovir was administered. During the patient’s hospitalisation, ocular inflammation and auricular chondritis occurred twice (Fig. 3A–C). The patient became irritated and anxious. A blood test showed elevated levels of WBC, CRP, ESR, complement 3, 4 and immunoglobulin E. Laboratory data associated with connective tissue diseases were within the normal range. The CSF and serum were evaluated for neoplasm and infectious agents, including herpes simplex virus (HSV), with negative findings. Brain MRI showed lesions involving the white matter in the right periventricular area and the right temporal lobe (Fig. 1D and E). Abnormal signal was also detected in the bilateral auricles (Fig. 1F and G). An auricular cartilage biopsy revealed the infiltration of acute inflammatory
cells and cartilage degeneration (Fig. 2B). The patient was diagnosed as having encephalitis with RP and was treated with intravenous methylprednisolone, 200 mg daily for 5 days, followed by 120 mg daily. One week later, the symptoms of ocular inflammation and cauliflower ear disappeared (Fig. 3D–F), and the patient felt well. The patient was then administered a daily oral dose of 60 mg of prednisone and 100 mg of azathioprine. MRI performed 3 months after discharge revealed improved results. During a 6month follow-up, the patient remained well without neurologic disorders while continuing to receive prednisone, 25 mg per day, and azathioprine, 100 mg per day, orally.
2.3. Patient 3 A 52-year-old man with mental changes for 1 year and a lowgrade fever for 15 days presented with arthralgia, eye redness, headache, memory loss, difficulty in communicating, deafness, gait disorders and urinary incontinence. On admission, physical examination showed eye redness (Fig. 4A), hypertrophic tough auricles (Fig. 4B), memory loss, difficulty in communicating and understanding, slow responsiveness, acalculia, papilledema (Fig. 4D and E), cogwheel phenomenon and tremor in both upper extremities with slight hypertonia and a stiff neck. The Mini-Mental State Examination score was 17/30. A blood test revealed leukocytosis with elevated ESR and CRP levels. Laboratory data associated with connective tissue diseases were all negative. CSF tests revealed polymorphonuclear (PMN) and mononuclear pleocytosis with high intracranial pressure, low levels of glucose content and high levels of protein (Table 1). The CSF and serum were also evaluated for neoplasm and infectious agents, including tuberculosis (TB), and herpes simplex virus (HSV), with negative findings. Review of brain MRI and CT scans from the previous year indicated worsening ventricular enlargement (Fig. 1H–J) and abnormal signals in the bilateral auricles (Fig. 1K). Tuberculous meningitis was initially suspected, and 5 mg of intravenous dexamethasone per day was administered. Eye redness recurred with discontinued or decreased dexamethasone treatment. After 5 weeks of antituberculous
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Fig. 1. Axial MRI and CT scans of Patients 1, 2, 3, and 4. (A, B) Patient 1. (A) T2-weighted MRI (T2WI) showing lesions involving the white matter in the periventricular area (arrows), and homogeneous hyperintensity; and (B) with treatment, the lesion areas decreased (arrow), and the lateral ventricles enlarged (arrow). (C–G) Patient 2. (C) T2WI showing hyperintense lesions in the left hippocampus (arrow), and (D) coronal fluid-attenuated inversion recovery (FLAIR) and (E) T2WI showing homogeneous hyperintensity (arrows) and lesions involving the white matter in the right periventricular area (arrow) and the right temporal lobe (arrow); (F) diffusion weighted image (DWI) showing abnormal signal in the bilateral auricles (arrow), and (G) post contrast T1-weighted MRI (T1WI) showing enhancement of the bilateral auricles (arrows). (H–K) Patient 3. (H) T1WI MRI showing no abnormal signal; (I, J) Imaging 15 days before admission showing (I) CT scan showing enlarged lateral ventricles (arrow) and third ventricle; and (J) T1WI showing more obvious enlargement of the lateral ventricles (arrow); (K) DWI showing an abnormal signal in the bilateral auricles (arrow). (L–N) Patient 4. (L) CT scan (M) T2WI and (N) DWI showing normal scans except for an abnormal signal in the left auricle (arrow).
therapy, no effects were detected, and the diagnosis was questioned. An auricle biopsy demonstrated hyperplasia and chondrocyte derangement (Fig. 2C). In combination with the chronic auricular chondritis, ocular inflammation, arthralgia and histological findings, hydrocephalus arising from aseptic meningitis related to RP was diagnosed. Intravenous methylprednisolone, 500 mg daily, and intravenous human immunoglobulin, 30 g daily, were administered over 5 consecutive days; antituberculous therapy was discontinued. The patient’s neurological symptoms improved
considerably with the disappearance of conjunctivitis (Fig. 4C), softened auricles and the disappearance of arthralgia. On discharge, the patient’s condition was good, and a CSF study was normal except for slightly high opening pressure (Table 1). When 3 months later oral prednisolone was decreased to 20 mg per day, relatives of the patient reported that conjunctivitis and slow responsiveness recurred. A CSF study showed an opening pressure of 280 mmH2O without more available details concerning pleocytosis and protein level. The symptoms improved considerably after steroid pulse therapy.
Z.J. Wang et al. / Journal of Clinical Neuroscience 18 (2011) 1608–1615
Fig. 2. Biopsies of ear cartilage showing loss of basophilic staining in the cartilage matrix: (A) Patient 1 – infiltration of chronic inflammatory cells into cartilaginous and perichondrial tissues (hematoxylin and eosin [HE] stain; (B) Patient 2 – infiltration of acute inflammatory cells and degeneration of cartilage (HE stain); (C) Patient 3 – hyperplasia and derangement of chondrocytes (HE stain) and (D) inflammation of cartilage and surrounding tissues (HE stain). Scale bar represents 50 lm.
2.4. Patient 4 A 44-year-old woman with pain in the sternoclavicular, neck, back and sacroiliac joints, anorexia, fatigue, anxiety, insomnia and weight loss for 1 year presented with left ear pain and swelling and hoarseness for 1 week. No headache was reported. Physical examination revealed left auricle swelling, redness (Fig. 4F) and tenderness, neck stiffness, Brudzinski signs and bilateral Kernig’s sign. A bone marrow puncture revealed bone marrow inflammation and hyperplasia of megakaryocytes. Blood tests revealed leukocytosis with anemia, thrombocytosis, and elevated ESR and CRP level. Laboratory data associated with connective tissue diseases were all within the normal range, except that the antinuclear antibodies (1:160) showed a speckled pattern. The CA 125 level was 267.8 l/mL (0.1–35 l/mL). Hypolipemia and hypoproteinemia were also observed. A CSF study showed mild mononuclear pleocytosis with mildly elevated levels of protein, a mildly
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decreased glucose content and normal opening pressure (Table 1). The CSF and serum were evaluated for neoplasm and infectious agents, including herpes simplex virus (HSV), TB, and Cryptococcus neoformans, with negative findings. The results of a laryngoscopy were normal. CT scans and brain MRI were both normal except for abnormal signal in the left auricle (Fig. 1L–N). Position emission tomography revealed slight hypermetabolism in the left ear and skeleton of the trunk but no hypermetabolism indicating a neoplasm. In combination with the auricular chondritis, and inflammation of peripheral joints and the fibrocartilage at axial sites and the larynx, cerebrospinal meningitis with RP was suspected. Intravenous methylprednisolone at a dose of 500 mg daily was administered, and the patient’s symptoms improved considerably. A flare-up in the left ear recurred when methylprednisolone was decreased to 120 mg per day. Consequently, methylprednisolone was decreased at a slower rate, and oral azothioprine was prescribed at a dose of 100 mg per day. Cauliflower ear also disappeared (Fig. 4G). After steroid therapy, a biopsy of the left ear still showed inflammation of the cartilage and surrounding tissues (Fig. 2D). On discharge, the results of the blood and CSF tests were almost normal, except that the CA 125 level was only reduced to 58.17 l/mL. The patient’s condition was good, and the symptoms had not recurred at the 3-month follow-up.
3. Discussion RP is a rare disorder characterised by recurrent episodes of inflammation of cartilaginous tissue. Any type of cartilage can be involved in RP, including auricular, nasal, tracheobronchial, valvular, and articular cartilage. RP can also involve other proteoglycanrich structures, such as the eyes, heart, blood vessels, inner ears and kidneys. The aetiology of RP is unknown. Type II collagen is most commonly involved.4 Both humoural and cellular immunity are thought to be involved. Most cases of RP are diagnosed in the fifth decade of life; the mean delay in diagnosis is 2.9 years. There is no gender difference. The diagnosis of RP is based primarily on clinical features. According to the criteria proposed by McAdam et al.,3 a diagnosis of RP can be established if three or more of the six clinical features (auricular chondritis, nonerosive inflammatory polyarthritis, nasal chondritis, ocular inflammation, respiratory tract chondritis or audiovestibular damage) are present along with positive histological findings. RP diagnosis can also be established if one or more of McAdam’s signs with positive histological confirmation are present or two or more separate anatomical locations are involved, along with a response to
Fig. 3. Patient 2. Photographs showing: (A) marked auricular swelling and redness; (B) bilateral conjunctivitis; (C) slit lamp image of conjunctivitis; (D–F) ear, eye, and slit lamp examination after steroid pulse therapy showing that the symptoms of ocular inflammation and cauliflower ear had disappeared.
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steroids and/or dapsone (diamino-diphenyl sulfone). This expanded criteria was proposed by Damiani and Levine; 5 according to them, histological examination of affected cartilage shows a loss of basophilic staining in the cartilage matrix, perichondrial
inflammation, and cartilage destruction with replacement by fibrous tissue. There is also lacunar breakdown and infiltration of neutrophils. As inflammation continues, there is condensation into irregular whorls of collagen with plasma cell and lymphocytic
Fig. 4. Patients 3 and 4. Patient 3 – photographs of symptoms and the fundus showing: (A) eye redness, (B) hypertrophic tough auricles, (C) the disappearance of eye redness and conjunctivitis, and (D, E) the fundus showing papilledema. Patient 4 – symptoms showing (F) left auricle swelling and redness (cauliflower ear), and (G) reduced auricular swelling on the left after treatment.
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infiltration. Chondrocytes dedifferentiate, forming fibroblasts and collagen fibres. Occasionally, small sites of cartilage regenerate. There is a loss of matrix acid mucopolysaccharides. The patients described in this study presented with auricular chondritis (Patients 1, 2, 3, and 4), ocular inflammation (Patients 1, 2, and 3), nonerosive inflammatory polyarthritis (Patients 1, 2, 3, and 4), laryngeal involvement (Patient 4), audiovestibular damage (Patient 1), and positive histological findings and their responses to steroids (Patients 1, 2, 3, and 4); these symptoms met the criteria proposed by both McAdam et al. and Damiani and Levine. Frostbite and infectious chondritis were excluded before the diagnosis of RP was made in our patients. We also excluded systemic lupus erythematosus, rheumatoid arthritis, Wegener’s granulomatosis, systemic sclerosis and paraneoplastic syndrome based on the clinical presentation and laboratory examinations. A few previous patients have been reported with meningoencephalitis with RP. A detailed search of all of the relevant English
language literature published between 1960 and 2010 via PubMed (http://www.ncbi.nlm.nih.gov/pubmed) was performed, using ‘‘relapsing polychondritis’’ and ‘‘nervous system’’ as keywords. Meningoencephalitis in patients with RP was found in 24 previous reports. The details of the 28 patients, including our four patients, are summarised in Table 2.6–26 Patient 1 had extensive white matter lesions that led to a psychiatric disorder and memory loss. Patient 2 first had a lesion in the left hippocampus, which led to amnesia; the mood disorder might have arisen from the temporal lobe lesion. The clinical manifestation was limbic encephalitis. The syndromes seen in Patient 3 could have been the result of raised intracranial pressure due to hydrocephalus arising from aseptic meningitis related to RP. The clinical manifestation in Patient 4 was aseptic cerebrospinal meningitis. The male-to-female ratio in the 28 patients was 19:9. The age of onset of meningoencephalitis related to RP was between 30 and 73 years. The average age of patients was 56 years. Including our four patients, 13 were
Table 2 Reports of patients with relapsing polychondritis and meningoencephalitis YearRef
Age/sex
Associated neurologic disorders (most cases had fever, headache or meningeal irritation signs)
Brain pathology
Response to steroid
Recurrent meningitis
19886
52/M
Generalized tonic-clonic seizure, impaired cognitive function, impaired visual acuity, hearing loss
Yes
Yes
Yes
19887
30/F 75/M 62/F
Hearing loss, unsteadiness Hearing loss, personality changes Hearing loss
No Yes No
Not used Yes Unknown
No No No
19928
73/F
Right ptosis, unilateral facial weakness, hearing loss
No
Yes
No
19949
70/F
Confusion, memory loss, unstable gait
No
Yes
No
199510
36/M
Diplopia, tinnitus, papilledema
No
Yes
No
199611
60/M
Ataxia, hearing loss, hydrocephalus
Yes
Yes
Yes
199612
70/M
Hearing loss, disturbances of consciousness
No
Yes
Yes
199813
66/M
Focal seizure
Yes
Yes
No
200414
57/M
Nystagmus, hearing loss, papilledema, memory loss
No
Yes
No
200415
49/M
Unsteady gait, somnolence, disorientation
No
Yes
No
200416
45/M
Disorientation, euphoria, confabulation, memory impairment Memory impairment, confusion, euphoria*
Yes
Yes
No
No
Yes
No
200517
57/F
Deafness, general convulsion, delirium, personality change
No
Yes
Yes
200618
53/M
Memory loss, cognitive impairment, aggressive and abusive behavior*
Yes
No
Yes
62/M
200619
71/F
Confusion, cerebral infarction
No
Yes
200720
40/M
Confusion
No
Yes
Unknown
200821
61/M
Loss of consciousness, convulsions, slurred speech, hallucination
No
Not used
Unknown
200822
66/F
Sleep inversion, tremor, urinary incontinence, gait disorder, memory disturbance, disorientation, akinetic mutism
No
Yes
No
200823
51/M
Coordination problems, distraction, word finding difficulty, emotional lability, jerking, confusion*
Yes
No
Die
200924
62/M
Generalized tonic-clonic convulsion, focal seizure
No
Yes
Yes
200925
56/F
Diplopia
No
Yes
No
201026
63/M
No
Yes
No
Current patients
54/M
No
Yes
Yes
No No
Yes Yes
Yes Yes
No
Yes
No
44/M 52/M
44/F *
Emotional disturbance, acoustic and visual hallucination, memory loss Memory loss, irritability, anxiety Anxiety, insomnia, memory loss, deafness, gait change, urinary incontinence, expressive and receptive aphasia, dullness, acalculia, and papilledema Anxiety, insomnia
No details regarding the presence of fever, headache and meningeal irritation signs were available.
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Caucasian and 15 were Mongolian. Thirteen patients suffered from meningoencephalitis during RP, meningoencephalitis and RP occurred simultaneously in six patients, and nine patients (including our Patients 1, 2, and 3) had an episode of meningoencephalitis before the diagnosis of RP. Early establishment of a diagnosis of meningoencephalitis with RP in this last group was a challenge for neurologists. At onset, most patients in this group had atypical manifestations of RP including dizziness, arthralgia, fever, weight loss and fatigue. When they developed meningoencephalitis, typical signs of RP were not reported or were neglected by doctors (such as occured in Patient 3). In this group, the interval between the onset of meningoencephalitis and the onset of the typical RP signs was from one day to fifteen months. In all cases, patients had clinical manifestations of fever, headache and signs of meningeal irritation. Associated neurological disorders included impaired cognitive function, memory loss, disorientation, expressive and receptive aphasia, dullness, acalculia, personality changes, euphoria, confabulation, hallucination, aggressive and abusive behaviour, disturbances of consciousness, confusion, somnolence, delirium, akinetic mutism, sleep inversion, insomnia, generalised tonic-clonic seizure, focal seizure, unstable gait, impaired visual acuity, papilledema, ptosis, diplopia, unilateral facial weakness, hearing loss, tinnitus, nystagmus, hemiplegia, and urinary incontinence (Table 2). CSF tests revealed pleocytosis in 26 patients, and two patients18,22 had no results. Seventeen patients, including our Patients 1, 2 and 4, showed pleocytosis with a predominance of mononuclear cells, including lymphocytes and monocytes in the CSF.6,7,9,10,14–16,19,21,23,24,26 Six patients showed pleocytosis with a predominance of PMN in the CSF.7,8,12,13,20,25 At first onset of meningoencephalitis, two patients showed pleocytosis with a predominance of mononuclear cells in the CSF, but the recurrences had a predominance of PMN 11,17 Our Patient 3 showed pleocytosis with a predominance of PMN in the CSF at first but later a predominance of mononuclear cells (Table 1). A predominance of PMN was observed in cases with more marked peripheral inflammation. This probably reflected the metabolic consequences of the peripheral manifestations of RP. Some patients presenting with limbic encephalitis or dementia showed lesions in the temporal lobes on MRI.14–16,18,20,23,24 Massry et al.10 reported that MRI in RP may be characterized by bilateral hypertensities in the basal ganglia. Addition of gadolinium enhanced smaller adjacent areas, an area in the left posterior thalamus, and a wedge-shaped area in the cortical grey matter. Three patients have been reported with leptomeningeal enhancement on contrast-enhanced T1-weighted MRI (T1WI).11,13,17 A patient with encephalitis lethargica with RP showed diffuse hyperintense lesions bilaterally in the basal ganglia on T2WI and fluid attenuated inversion recovery (FLAIR) images.22 All of our patients had abnormal signals in the affected auricle on MRI and CT scans, which is similar to the ‘‘prominent ear sign’’ described by Kuwabara et al.21 A biopsy or autopsy of the brain was performed in seven of the 24 previously reported patients summarised in Table 3.6,7,11,13,16,18,23 The aetiology of central nervous system
(CNS) involvement in RP patients is still unknown but seems to originate from autoimmunity. Antibodies to type II collagen have been found in some RP patients. Thus, Brod et al. speculated that remnants of the notochord could serve as antigens in the CNS. They also speculated that an antigen distinct from collagen could be involved in the CNS and that vasculitis could be the cause of neurological disorders in some patients with RP.8 Stewart et al. described diffuse vasculitis of the brain.6 Massry et al. suggested that cerebral arteritis was associated with RP after analysing the brain MRI of a patient with RP.11 Ragnaud et al. reported that, in a patient suffering from generalised maculopapular eruptions, a biopsy revealed cutaneous vasculitis.12 These studies showed a strong relationship between vasculitis and neurological disorders in some patients with RP. Kashihara et al. found that autoantibodies to the GluRe2 (NR2B) subunit could be associated with limbic encephalitis in certain patients with RP.24 Our four patients declined to undergo a brain biopsy. We speculate that vasculitis or non-specific inflammation may have involved the leptomeninges and the parenchyma of the brain in our four patients. A standardised therapeutic protocol for RP has not been established because of its rarity, the diversity of presentations, the unpredictable recurrence rate and course, and the potential CNS involvement. Corticosteroids are the predominant treatment of choice but cannot stop the progression of the disease or vital organ involvement. Life-threatening complications can occur after repeated relapses and severe ocular involvement. In such instances, immunosuppressive therapy along with systemic steroids and cytotoxic agents are required. Of the 28 reported meningoencephalitis patients with RP, 23 responded to steroid therapy, two did not respond to steroid therapy, and nine displayed recurrent meningitis (Table 2). Systemic steroids were administered to our four patients. Because of the delay in diagnosis, Patient 1 received systemic steroid treatment after two relapses involving the cerebral parenchyma. The clinical manifestations and lesions observed on MRI improved slowly. Patient 2 received systemic steroids early and had no irreversible lesions in the cerebral parenchyma. Although he was disturbed by eye inflammation after hospital discharge, there were no severe sequelae of the CNS. Patient 3 had no obvious lesions in the cerebral parenchyma, and his manifestations arose from raised intracranial pressure due to hydrocephalus. Although the diagnosis was delayed by 1 year, the manifestations improved considerably after systemic steroid therapy. Patient 4 had a long period of atypical RP manifestations without CNS involvement. When aseptic meningitis was diagnosed, steroids were immediately administered and recovery was quick and complete. Concerning systemic steroid therapy, intravenous methylprednisolone should be administered at a dose of 500 to 1000 mg per day for 3 to 5 days and then decreased to a dose of 125 mg per day, followed by oral prednisone at 60 mg per day for 4 weeks (which should then be decreased at a rate of 10 mg every 2 weeks). The administration of cytotoxic agents such as azathioprine may help to reduce the steroid dosage required. Systemic steroids were administered to our four patients, and 100 mg daily of oral azathi-
Table 3 Brain biopsy or autopsy results in patients with relapsing polychondritis and meningitis YearRef
Pathological description
19886 19887 199611 199813 200416
Diffuse vasculitis of the brain Lymphocytic infiltration in the meninges Inflammatory cells without evidence of granulomas; fungal, bacterial and mycobacterial stains and cultures were negative No evidence of vasculitis, although inflammatory changes in the meninges and the cerebral parenchyma were noted Inflammatory cell components consistent with meningoencephalitis which were predominantly T cells, and the histopathological features were not specific for vasculitis Neuronal loss, gliosis and microgial nodules in the hippocampus, cingulate gyrus, temporal and occipital lobes, patchy perivascular cuffing, and leptomeningeal lymphocytic infiltrates in the cerebral cortex, striatum, thalamus and medulla Non-specific inflammation without evidence of vasculitis
200618 200823
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oprine was administered to Patients 1, 2 and 4. The length of treatment depends on the clinical manifestations. 4. Conclusion Meningoencephalitis with RP is a rare condition. The diagnosis is challenging because of its rarity and the diversity of clinical presentations. Our presented patients and literature review emphasise the need for early diagnosis and initiation of immunosuppressive treatment. If specific treatment is delayed, severe sequelae may result during flare-ups of RP. The aetiology of meningoencephalitis associated with RP merits further investigation. References 1. Jaksch-Wartenhorst R. Polychondropathia. Wien Arch Intern Med 1923;6:93–100. 2. Pearson CM, Klene HM, Newcomer VD. Relapsing polychondritis. N Engl J Med 1960;263:51. 3. McAdam LP, O’Hanlan MA, Bluestone R, et al. Relapsing polychondritis: prospective study of 23 patients and a review of the literature. Medicine 1976;55:193–215. 4. Foidart JM, Abe S, Martin GR, et al. Antibodies to type II collagen in relapsing polychondritis. N Engl J Med 1978;299:1203–7. 5. Damiani JM, Levine HL. Relapsing polychondritis – report of ten cases. Laryngoscope 1979;89:929–46. 6. Stewart SS, Ashizawa T, Dudley AW, et al. Cerebral vasculitis in relapsing polychondritis. Neurology 1988;38:150–2. 7. Brod S, Booss J. Idiopathic CSF pleocytosis in relapsing polychondritis. Neurology 1988;38:322–3. 8. Wasserfallen JB, Schaller MD. Unusual rhombencephalitis in relapsing polychondritis. Ann Rheum Dis 1992;51:1184. 9. Hanslik T, Wechsler B, Piette JC, et al. Central nervous system involvement in relapsing polychondritis. Clin Exp Rheumatol 1994;12:539–41. 10. Massry GG, Chung SM, Selhorst JB. Optic neuropathy, headache, and diplopia with MRI suggestive of cerebral arteritis in relapsing polychondritis. J Neuroophthalmol 1995;15:171–5.
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