Dimitri Renard

Long-term Outcomes of CLIPPERS (Chronic Lymphocytic Inflammation With Pontine Perivascular Enhancement Responsive to Steroids) in a Consecutive Series of 12 Patients

BACKGROUND Chronic lymphocytic inflammation with pontine perivascular enhancement responsive to steroids (CLIPPERS) is a central nervous system inflammatory disease. OBJECTIVE To describe the disease course of CLIPPERS. DESIGN A nationwide study was implemented to collect clinical, magnetic resonance imaging, cerebrospinal fluid, and brain biopsy specimen characteristics of patients with CLIPPERS. SETTING Academic research. PATIENTS Twelve patients with CLIPPERS. MAIN OUTCOME MEASURES The therapeutic management of CLIPPERS was evaluated. RESULTS Among 12 patients, 42 relapses were analyzed. Relapses lasted a mean duration of 2.5 months, manifested frequent cerebellar ataxia and diplopia, and were associated with a mean Expanded Disability Status Scale (EDSS) score of 4. Besides typical findings of CLIPPERS, magnetic resonance imaging showed brainstem mass effect in 5 patients, extensive myelitis in 3 patients, and closed ring enhancement in 1 patient. Inconstant oligoclonal bands were found on cerebrospinal fluid investigation in 4 patients, with an increased T-cell ratio of CD4 to CD8. Among 7 available brain biopsy specimens, staining was positive for perivascular CD4 T lymphocytes in 5 samples. Thirty-eight of 42 relapses were treated with pulse corticosteroid therapy, which led to improvement, with a mean residual EDSS score of 1.9 (range, 0-7). In 1 patient with untreated relapses, scores on the EDSS progressively increased to a score of 10 at death. Among 5 patients without long-term corticosteroid therapy, the mean annualized relapse rate was 0.5 (range, 0.25-2.8). Among 7 patients taking oral corticosteroids, no relapses occurred in those whose daily dose was 20 mg or higher. No progressive course of CLIPPERS was observed. Four patients with a final EDSS score of 4 or higher had experienced previous severe relapses (EDSS score, ≥5) and brainstem and spinal cord atrophy. CONCLUSIONS CLIPPERS is a relapsing-remitting disorder without progressive forms. Long-term disability is correlated with the severity of previous relapses. Further studies are needed to confirm that prolonged corticosteroid therapy prevents further relapses.

Reversible posterior leucoencephalopathy during oral treatment with methotrexate

Sirs: Posterior reversible leucoencephalopathy (PRLE) is a wellknown complication of intravenous or intrathecal treatment with high doses of methotrexate [2–4, 6]. We report a case of PRLE following long-term low-dose administration via the oral route. A 49 year old woman experienced slowly progressive visual and motor disturbances for 5 months. She reported blurred vision, difficulty in recognizing faces or seeing objects as a whole, reading problems, as well as difficulties when reaching with her left arm. She had had psoriatic arthritis since the age of 35 years, type II diabetes mellitus since the age of 48, and was diagnosed with Hashimoto thyroiditis at the age of 48. Current medication consisted of oral methotrexate 7.5 mg once a week since the age of 42 (cumulative dose of 2730 mg), atorvastatine 10 mg three times a week, omeprazole 10 mg o.d. for 6 months, levothyroxine 50 μg o. d., propamide 125 mg bid, bromazepam 3 mg o. d., propranolol 80 mg o. d., and folic acid 1 mg o. d. Because the recent neurological problems were originally attributed to a cerebrovascular cause, her referring physician also started a combination of acetylsalicylate 25 mg bid and dipyridamol 200 mg bid. Prior treatment for psoriatic arthritis included oral gold between the age of 35 and 42 and steroids and non steroidal anti-inflammatory drugs around the age of 40. At the age of 43, liver function tests had been transiently and mildly elevated, which was attributed after liver biopsy to methotrexate therapy. During the past year she had experienced a 2 months period of cough and dyspnea interpreted as possible interstitial pulmonary disease after chest radiography and pulmonary function tests. This resolved spontaneously. There was no history of hypertension or substance abuse. On clinical neurological examination her speech was slow but wellarticulated. Visual fields were normal on confrontation testing. Visually guided saccades were within the normal range. Muscle strength and tone as well as tendon reflexes were intact, with plantar responses in flexion. She could not reach with her left hand for objects presented in left or right visual field. She could write but was unable to read her own writing (alexia without agraphia). She read words of more than 4 letters letter-by-letter. She could not draw from memory or copy a clock or a cube. Blood pressure was within the normal range. Neuropsychological examination, including among other tests the Visual Object and Space Perception Battery, the Birmingham Object Recognition battery [5] as well as Beery’s visuomotor integration test [1] confirmed the presence of severe visuoperceptual, visuospatial and visuoconstructional deficits. Magnetic resonance imaging (MRI) revealed extensive T2 and Fluid Attenuated Inversion Recovery (FLAIR) hyperintensities in the ventral occipitotemporal white matter bilaterally and in the right superior parietal lobule (see Fig. 1). MR angiography of the intraand extracranial vasculature was negative. CSF was normal (white blood cell count of 0.8 cells/μl, protein concentration of 545 g/l and a glucose level of 55 mg/dl – with a glucose serum level of 98 mg/dl – without intrathecal IgG synthesis). PCR for JC virus in CSF and urine were negative. Complete blood count revealed a mild pancytopenia with hemoglobin of 10.4 g/dl [12–16], mild macrocytosis (MCV 97.5 fl [76–96]), leucocytes of 3.1 109/l [4–10], and thrombocytes of 120 109/l [150–450]. A bone marrow puncture revealed mild erythroid hyperplasia and mild dysplastic features of the myeloid and megakaryocytic cell lineages, consistent with intake of methotrexate. Kidney function, lipidemia, sedimentation rate, ANF, lupus anticoagulans, ANCA, vitamin B12, thyroid function, and lactic acid were normal. Homocystein level was 14.5 μmol/l [6–13]. Thyroid peroxidase antibody levels were elevated (879 kU/l, with normal values between 0 and 100 kU/l). Serology of HIV, EBV, CMV and JC virus, Borrelia, and syphilis was negative. Electrocardiography, transesophagal echocardiography and 24-hours cardiac monitoring were normal. We stopped oral methotrexate while keeping the remaining medication. Over the following 6 months the clinical picture regressed almost entirely. Neuropsychological re-evaluation 5 months after stopping methotrexate using the same tests could no longer reveal any abnormalities. MRI examinations at 1, 4 and 12 months after stopping methotrexate showed regression of the ventral and the parietal lesions (see Fig. 1). To the best of our knowledge this is the first report of posterior leucoencephalopathy following oral treatment with methotrexate at a low dose given for a prolonged period of time with documented LETTER TO THE EDITORS

Cannabis-Related Myocardial Infarction and Cardioembolic Stroke

We report a 33-year-old man with a history of chronic cannabis use who sustained myocardial infarction followed by cerebral infarction after a recent significant increase in cannabis use. This is the first case of cannabis-associated stroke of probable cardioembolic origin.

A new case of chronic lymphocytic inflammation with pontine perivascular enhancement responsive to steroids with initial normal magnetic resonance imaging

Sir, We read with great interest the recent article published in Brain by Pittock et al. (2010), who reported eight patients with clinical, radiological and pathological features of brainstem involvement responsive (but dependent) to steroid treatment. All the reported patients shared common clinical and MRI findings: gait ataxia, diplopia, patchy increased T2 signal and gadolinium enhancement within the pons and the middle cerebellar peduncles, the presence of oligoclonal bands on CSF analysis, and normal cerebral angiography. Involvement of the medulla, the cerebellum, the midbrain, the basal ganglia, the corpus callosum and the spinal cord has also been described. Brain biopsy of four patients found white matter T-lymphocytic infiltrate with perivascular predominance. Steroids led to clinical and neuroradiological improvement in all patients, with steroid dependency in three (mean follow-up: 22 months, range: 7–144 months). CLIPPERS (acronym for chronic lymphocytic inflammation with pontine perivascular enhancement responsive to steroids) was proposed to …

Subacute combined degeneration of the spinal cord caused by nitrous oxide anaesthesia

Vitamin B12 deficiency causes haematological, gastrointestinal and neurological diseases. Subacute combined degeneration (SCD) of the spinal cord is characterised by degeneration of the posterior and lateral columns. We report a case of SCD associated with nitrous oxide anaesthesia.

An MRI review of acquired corpus callosum lesions

Lesions of the corpus callosum (CC) are seen in a multitude of disorders including vascular diseases, metabolic disorders, tumours, demyelinating diseases, trauma and infections. In some diseases, CC involvement is typical and sometimes isolated, while in other diseases CC lesions are seen only occasionally in the presence of other typical extra-callosal abnormalities. In this review, we will mainly discuss the MRI characteristics of acquired lesions involving the CC. Identification of the origin of the CC lesion depends on the exact localisation of the lesion(s) inside the CC, presence of other lesions seen outside the CC, signal changes on different MRI sequences, evolution over time of the radiological abnormalities, history and clinical state of the patient, and other radiological and non-radiological examinations.

Myocardial infarction after rituximab infusion

Myocardial infarction after rituximab or other monoclonal antibody therapies has been reported in rare cases, all in patients with classical cardiovascular risk factors or associated inflammatory or lymphoproliferative disorders. We report the case of a 52-year-old man, without classical cardiovascular risk factors or associated inflammatory or lymphoproliferative disorder, treated for seronegative myasthenia with rituximab infusions complicated by myocardial infarction. The exact origin of myocardial infarction after monoclonal antibody treatment is unclear. Myocardial infarction is a rare but possibly fatal complication of rituximab infusion, even occurring in relatively young patients, without classical risk factors and without associated inflammatory or lymphoproliferative disorder.

4H syndrome: a rare cause of leukodystrophy.

A 24-year-old woman suffered from gait unsteadiness and tetraparesis since childhood. Her medical history was characterized by a normal delivery of non-consanguineous parents. Walking with support was acquired at 10 months. Childhood development was characterized by occurrence of a progressive cerebellar ataxia, short stature, mental development retardation (IQ = 46), and hypodontia (i.e., absence of deciduous teeth eruption and short tooth roots). Walking without support was never acquired. At the age of 14, a partial growth hormone (GH) deficit (insufficient peak of GH in standard condition and with stimulation tests) and an hypogonadotropic hypogonadism [absence of luteinizing hormone (LH) and follicle stimulating hormone (FSH), lack of response to LH-releasing hormone (LH-RH) injection with LH peak at 0.6 UI/l and FSH peak at 1.4 UI/l] were found. Dental panoramic radiographs showed short tooth roots and absence of dental pulp chamber (Fig. 1). At the age of 24, neurological examination observed a severe static and kinetic cerebellar syndrome, spastic tetraparesis, multidirectional nystagmus, vertical down and up-gaze palsy, and mental retardation. Walking perimeter was 10 m with human assistance. Neuro-ophthalmologic examination confirmed vertical gaze palsy, and revealed amblyopia (with visual acuity of 4/10 on both sides), severe myopia, and bilateral temporal papillary atrophy. Nerve conduction studies and electromyography were normal. Neuroimaging performed at 3 Tesla (Philips, Best, The Netherlands) showed marked atrophy of the corpus callosum (reflecting the global white matter (WM) volume) and the cerebellum. In addition, spinal cord atrophy was moderate (data not shown). Myelinated areas including the pyramidal tracts, the internal capsule, the deep cerebellum, and the brainstem were hyperintense relative to cortical grey matter (CGM) on T1-WI and hypomyelinated areas (=rest of the white matter) were diffusely hypointense relative to CGM on T1-W1 (Fig. 2a–c). On T2-FLAIR images, the myelinated area appeared iso/hypointense relative to CGM and the hypomyelinated area appeared diffusively hyperintense relative to CGM (Fig. 2d–f). The pons appeared small with widening of the prepontine cystern, which was probably due to hypomyelinated corticopontine tracts as well as atrophy of crossing cerebellar tracts (Fig. 2a, c, d, f). Single voxel proton-magnetic resonance spectroscopy (HMRS) spectra showed low choline/creatine and N-acetylaspartate/creatine ratios within the left semi-ovale WM, left basal ganglia and pons. A prominent myo-inositol peak was also found within the pons (Fig. 2g). Tractography obtained from a Diffusion O. Outteryck (&) D. Devos L. Hopes P. Vermersch Department of Neurology, Salengro Hospital, Universite Lille Nord de France, CHRU Lille, Rue Emile Laine, 59037 Lille Cedex, France e-mail: Olivier_outteryck@hotmail.com

Brain MRI findings in long-standing and disabling multiple sclerosis in 84 patients

OBJECTIVE To look for cerebral white matter MRI changes in patients with long-standing and disabling MS. METHODS We analyzed retrospectively brain MRIs (performed 10 or more years after symptom onset) of patients with MS diagnosis and expanded disability status scale of 6 or more. The following parameters were analyzed: total number of brain T2 hyperintensities; number of brainstem, cerebellar, corpus callosum, basal ganglia, and juxtacortical T2 hyperintensities; diffuse leukoencephalopathy score; total number of T1 hypointensities. RESULTS Eighty-four patients were included. The mean time between symptom onset and MRI was 20.2 years. Eight percent had less than 9 cerebral T2 hyperintensities. Posterior fossa, juxtacortical, and corpus callosum T2 hyperintensities, and T1 hypointensities lacked in respectively 19%, 12%, 47%, and 8%. Overall, normal MRI was not seen, 6% had abnormal MRI but did not meet Barkhofs criteria, and the remaining 94% had MRI abnormalities fulfilling Barkhofs criteria. Moderate or severe diffuse leukoencephalopathy was seen in 69%. Extensive diffuse leukoencephalopathy predominant to nodular lesions was seen in 5%. CONCLUSIONS Despite long-standing and disabling MS, typical MRI abnormalities lacked in a minority of patients, and 6% did not fulfil Barkhofs criteria. The majority showed moderate or severe diffuse leukoencephalopathy.

A MANBA mutation resulting in residual beta-mannosidase activity associated with severe leukoencephalopathy: a possible pseudodeficiency variant.

Backgroundβ-Mannosidosis (OMIM 248510) is a rare inborn lysosomal storage disorder caused by the deficient activity of β-mannosidase, an enzyme encoded by a single gene (MANBA) located on chromosome 4q22-25. To date, only 20 cases of this autosomal recessive disorder have been described and 14 different MANBA mutations were incriminated in the disease. These are all null mutations or missense mutations that abolish β-mannosidase activity. In this study, we characterized the molecular defect of a new case of β-mannosidosis, presenting with a severe neurological disorder.MethodsGenomic DNA was isolated from peripheral blood leukocytes of the patient to allow MANBA sequencing. The identified mutation was engineered by site-directed mutagenesis and the mutant protein was expressed through transient transfection in HEK293T cells. The β-mannosidase expression and activity were respectively assessed by Western blot and fluorometric assay in both leukocytes and HEK293T cells.ResultsA missense disease-associated mutation, c.1922G>A (p.Arg641His), was identified for which the patient was homozygous. In contrast to previously described missense mutations, this substitution does not totally abrogate the enzyme activity but led to a residual activity of about 7% in the patients leukocytes, 11% in lymphoblasts and 14% in plasma. Expression studies in transfected cells also resulted in 7% residual activity.ConclusionCorrelations between MANBA mutations, residual activity of β-mannosidase and the severity of the ensuing neurological disorder are discussed. Whether the c.1922G>A mutation is responsible for a yet undescribed pseudodeficiency of β-mannosidase is also discussed.