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- brain biopsy
- immunosuppressant therapy
- limbic encephalitis
- psychiatric symptoms
- relapsing polychondritis
Relapsing polychondritis is a generalised disorder characterised by recurrent inflammation of cartilaginous structures throughout the body, without recognised collagen disease or infectious disorders. Central nervous system involvement is rarely reported in this disorder. We describe the cases of two patients with relapsing polychondritis who presented with severe memory impairment and psychiatric features such as euphoria and hyperactive behaviours, leading to a diagnosis of non-herpetic limbic encephalitis.
Limbic encephalitis is caused by the herpes simplex virus (HSV) or by heterogeneous non-herpetic disorders (non-herpetic viruses, Hashimoto’s encephalopathy, central nervous system lupus, gliomatosis cerebri, intravascular malignant lymphomatosis, and paraneoplastic conditions). Clinical characteristics include cognitive dysfunction, severe memory impairment, seizures, depression, anxiety, and hallucinations. Magnetic resonance imaging (MRI) studies reveal selective unilateral or bilateral involvement of the limbic system, particularly the medial temporal lobe regions.
Our first patient was a 45 year old man referred to us because of subacute progressive mental confusion, euphoria, hyperactive behaviour, disorientation, and forgetfulness of recent episodes. He had a history of right sided conjunctivitis successfully treated with steroid and antibiotic ointment, shoulder stiffness, headache, low grade fever, and recent weight loss (6 kg).
On admission, the patient was disoriented, with an inappropriately jocular affect, disjointed speech, confabulation, attention deficits, and memory impairment including anterograde and 1 year retrograde amnesia. His Mini Mental Status Examination (MMSE) score was 11 (of a possible 30). He had no pyramidal or extrapyramidal disturbances or cerebellar ataxia. T2 weighted MRI showed bilateral, small, disseminated high intensity signals with vague margins in the medial temporal lobe, hippocampus, and insular cortex (fig 1A).
Laboratory studies showed white blood cell count 14.8×109/l (normal 3.9–9.3×109/l), platelet count 363×109/l, β-thromboglobulin (β-TG) 94 μg/l (normal <50 μg/l), platelet factor 4 (PF-4) 30 ng/ml (normal <20 ng/ml), erythrocyte sedimentation rate (ESR) 42 mm/h, C reactive protein (CRP) 29 mg/l, ferritin 668 μg/l (normal <465 ng/ml), rheumatoid factor 145 IU/ml (normal <20), and antinuclear antibodies (ANA) 1:40. Serum tests were negative for myeloperoxidase antineutrophil cytoplasmic antibodies, anti-DNA, anti-SSA/SSB, and anti-RNP. Thyroid function and vitamin B1 and B12 levels were normal. Syphilis, HSV-1, HSV-2, herpes zoster virus, human herpes virus 6, cytomegalovirus, Epstein-Barr virus, measles, rubella, and mumps were serologically excluded. No neoplasm was detected. Cerebrospinal fluid (CSF) was sterile, with a protein concentration of 86 mg/dl; glucose, 3.0 mmol/l (serum glucose, 5.5 mmol/l); white cells, 8×109/l (94% lymphocytes); and IgG/albumin index, 1.02.
Despite intravenous acyclovir, his cognitive function deteriorated, and his MMSE score decreased to 4. He developed right conjunctivitis, left wrist pain, and bilateral auricular swelling. Brain biopsy showed marked gliosis with scattered gemistocytic astrocytes, perivascular cuffing, and destruction of the vascular wall (fig 1B). After high dose intravenous methylprednisone, then 40 mg oral prednisone per day, his psychiatric and cognitive functions improved dramatically and the joint pain and auricular swelling disappeared. Mild impairment of recent memory and orientation remained. MRI performed 1 month later revealed bilateral cortical atrophy in the temporal lobes with dilated temporal horns.
Our second patient was a 62 year old man who presented with subtle memory impairment, confusion, and euphoria, with a history of ankle and wrist pain. On examination, he had mild hearing loss and bilateral auricular swelling. Although appearing alert and happy, he had amnesic episodes, was disoriented, and had impairment of memory storage and calculation (MMSE score 4). He followed simple commands, but filled in memory gaps with inaccurate and implausible information. All other neurological findings were unremarkable.
Laboratory examination showed ESR 20 mm/h, CRP 12 mg/l, IgE 1570 IU/l, fibrinogen 5.51 g/l, and ferritin 448 μg/l. Thyroid function and serum vitamin B1 and B12 levels were normal. Results were negative for all bacterial, mycobacterial, fungal, and viral stains and cultures, and for specific antigen tests. Whole body computed tomography and gallium scintigrams to search for neoplasms in the lungs, thymus, and testis and for haematological malignancies yielded negative results. CSF examination showed increased white cell count 24×109/l (83% lymphocytes), protein 46 g/l, glucose 4.27 mmol/l (serum glucose 5.94 mmol/l), and IgG/albumin index 1.56 (normal <0.6).
Fluid attenuated inversion recovery (FLAIR) images and T2 weighted MRI revealed bilateral, sparse, high intensity patches in the mediotemporal lobe, including the insula, hippocampus, and amygdala, and abnormal signals in the deep white matter. Auricular biopsy showed active chondritis. Brain biopsy demonstrated prominent perivascular cuffing around the meningeal and intracerebral vessels with increased vascular wall thickness.
After methylprednisone pulse therapy and then 40 mg per day of prednisone orally, the auricular swelling lessened and the psychiatric problems improved enough for the patient to communicate verbally. However, after 2 months, recent memory storage and orientation were still impaired and MRI showed bilateral cortical atrophy within the frontotemporal lobes.
Both patients had auricular chondritis, ocular inflammation, and non-erosive polyarthritis, thus meeting the criteria for a diagnosis of relapsing polychondritis.1 In addition, the clinical manifestations, radiological findings, and absence of HSV infections indicated non-herpetic limbic encephalitis. Despite intensive investigation, no evidence of a neoplasm or a known autoimmune disease was found.
Several previous case reports of relapsing polychondritis include confusion, disorientation, and psychiatric symptoms with or without neurological abnormalities,2–5 suggesting that limbic system involvement might be more common in this disorder than is generally thought. Histopathological evidence is limited. Although extensive cerebral and systemic vasculitis has been demonstrated on autopsy,2 an inflammatory cell component has not been demonstrated.
In our patients, simultaneous brain and auricular biopsies showed active inflammation with chondritis and meningoencephalitis. The inflammatory cell components consistent with meningoencephalitis were predominantly T cells. Although our observations of perivascular cuffing with increased thickness and partial destruction of the vascular wall were consistent with vasculitis, the histopathological features were not specific for vasculitis.
Our patients responded dramatically to early treatment with high dose intravenous corticosteroids followed by an oral corticosteroid, although mild amnesia with confabulation remained in both cases. The atrophy of the medial temporal lobe and dilatation of the temporal horns of the lateral ventricle seen on MRI after treatment indicated irreversible ischaemic damage. Although we cannot exclude the possibility that the brain atrophy in the medial temporal regions resulted from the corticosteroid therapy, bilaterally reduced blood flow was seen on SPECT images of the temporal lobes (data not shown), suggesting that the atrophy was not caused by corticosteroid treatment.
Although relapsing polychondritis is a rare disorder, it should be considered in the differential diagnosis of neurological complications such as limbic encephalitis, and it is worth noting that steroid therapy may be beneficial.
Competing interests: none declared
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