Delayed and recurrent dimethyl fumarate induced-lymphopenia in patients with multiple sclerosis.

BACKGROUND: Early lymphopenia is a known side effect of dimethyl fumarate, a disease-modifying therapy for MS. However, the long-term effects on immune response and the impact on lymphocyte counts when another disease-modifying treatment is introduced, remain unknown. To better understand these specific aspects, we reviewed cases that develop prolonged grade 2 to 4 lymphopenia under dimethyl fumarate in Lausanne MS clinic. METHOD: Retrospective analysis of the 12 patients (10.1%) who discontinued dimethyl fumarate because of prolonged lymphopenia amongst the 119 patients treated with dimethyl fumarate. We reviewed their demographics, as well as their clinical, biological and MRI characteristics compared to the non-lymphopenic patients, during dimethyl fumarate therapy, and within a timeframe of up to 18 months after switching to another disease-modifying treatment. We also focused on lymphocyte subsets in a subgroup of patients. RESULTS: Compared to non-lymphopenic patients, lymphopenic patients were older at dimethyl fumarate initiation (51.4 yo vs 39.7, p = 0.0003) and the majority were male (p = 0.037). Three of them (25%) developed delayed lymphopenia, more than one year after treatment onset. Despite persistent lymphopenia, three patients experienced disease activity. Amongst the nine patients (75%) who were switched to another therapy, five (55.6%) presented recurrent lymphopenia, predominantly with a CD8+ T cell decrease. CONCLUSIONS: Dimethyl fumarate has a long-term impact on lymphocyte biology, even after its discontinuation, with a sustained reduction in CD8+ T cells that may increase opportunistic infection risk, and should be taken in consideration when switching therapies after dimethyl fumarate.

Is disease activity prior to fingolimod initiation predictive of response? Fingolimod as a "common" first line treatment.

BACKGROUND: In countries where fingolimod is available as first-line therapy without restrictions, we have an opportunity to observe long-term efficacy profile of this drug in treatment-naive patients according to their initial disease activity. METHODS: We retrospectively analysed the data of RRMS patients treated with FTY, focusing on 2 groups: 17 highly active patients (HA) defined as follows: ≥2 relapses in the year before treatment initiation and either≥1 Gd-enhancing T1 lesion or a significant increase in T2 lesion load from a baseline MRI; and 37 "not highly active" (NHA). We reviewed treatment efficacy (defined as NEDA-3), reasons for discontinuation and treatment tolerance in both groups. RESULTS: Mean follow-up duration was 48.2 months, SD 18.4. Fingolimod efficiently reduced relapses (NHA 90.3% reduction, P<0.001, HA 84.9%, P<0.001), and new Gd enhancing lesions (NHA 85.4% reduction, P=0.019, HA 92.3%, P=0.043). The proportion of patients reaching NEDA-3 status was higher in the NHA group (NHA: 80% at 2 years and 66% at 4 years, HA: 58% at 2 years and 38% at 4 years, P=0.042). Fingolimod was discontinued in 20 cases, mainly because of lack of efficacy (n=15). CONCLUSIONS: FTY is efficient in reducing relapses and new Gd enhancing lesions in both HA and NHA patients although the probability of achieving NEDA-3 over time is higher in early-treated treatment-naive NHA patients.

First-ever treatment in multiple sclerosis.

BACKGROUND: The current treated MS population is very different from that of patients in randomized clinical trials. OBJECTIVES: To study the long-term efficacy and tolerance of fingolimod (FTY) and dimethyl fumarate (DMF), both available as first-line treatment in early-treated treatment-naïve MS patients. METHODS: Retrospective analysis of 75 patients from our prospective MS registry fulfilling the inclusion criteria: FTY or DMF as first-line treatment, treatment initiation within 36months of disease onset and treatment duration>12months. RESULTS: Demographics and MRI characteristics at baseline were similar in both groups (FTY 55 patients, DMF 20), but patients on FTY had higher pretreatment clinical activity (P=0.008). Twenty-two percent of patients in the FTY group and 15% in the DMF group had highly active disease. At last follow-up (mean: 44.2, SD: 17.3months), the majority of the patients were still on treatment while 54.5% of FTY and 65% of DMF patients reached NEDA 3 status (P=0.444). Both treatments significantly decreased relapses and occurrence of new T1 Gd-enhancing lesions (P<0.001). The main reason for discontinuation was disease activity without severe side effects on either treatment. CONCLUSIONS: Our findings support efficacy and tolerance of both drugs in early-treated treatment-naive MS patients, arguing in favour of efficient early immunomodulation in MS patients. Both drugs significantly reduced the incidence of new relapses and Gd-enhancing lesions on treatment with FTY being more frequently prescribed than DMF, especially in patients with evidence of higher clinical disease activity.

Ulnar neuropathy at the elbow: Reappraisal of the wrist-upper arm latency difference between ulnar and median nerves.

OBJECTIVES: To evaluate the sensitivity and specificity of the latency difference (DLat) between ulnar and median nerves of the arm after stimulation at the wrist; one of the easiest techniques proposed for recognizing ulnar neuropathy at the elbow (UNE). As latency difference is not a standardized technique, we set up a multicenter study to recruit large numbers of normal subjects and patients with UNE or generalized neuropathy. METHODS: Six centers participated in the study with data obtained from three groups of participants, controls (CTRLs), patients with UNE and patients with generalized neuropathy (GNP). We first verified the anatomical superposition of the ulnar and median nerves in cadaver examination. The optimal recording site for these two nerves was found to be 10 cm above the medial epicondyle. We then standardized the position of the arm with full extension of the elbow and stimulated first the median and then the ulnar nerves at the wrist. CTRLs were examined on both arms at two consecutive visits. RESULTS: We recorded 32 idiopathic UNE cases, 44 GNP patients and 62 controls. We demonstrated that a DLat cut-off value of 0.69 ms brings a sensitivity of 0.86 and specificity of 0.89 to discriminate CTRLs from UNE. We also validated that intra-examiner reproducibility was good. CONCLUSION: We report a lower normal value for DLat than reported in several non-standardized studies and CTRL and UNE groups have clearly separated DLat values. SIGNIFICANCE: Due to its high sensitivity, our standardized technique could be used as a first-line diagnostic tool when UNE is suspected.

Upper limb onset of hereditary transthyretin amyloidosis is common in non-endemic areas.

BACKGROUND AND PURPOSE: The aim is to describe an uncommon phenotype of hereditary ATTR neuropathy with upper limb onset. METHODS: The French TTR Familial Amyloid Polyneuropathy database was used for a retrospective evaluation of 32 consecutive patients with upper limb onset of the neuropathy (study group) and they were compared to 31 Portuguese early-onset patients and 99 late-onset patients without upper limb onset. RESULTS: Initial upper limb symptoms were mostly sensory. Lower limb symptoms began 2.3 ± 3 years after upper limb symptoms. Twenty-four (75%) patients were initially misdiagnosed, with 15 different diagnoses. More patients in the study group had a Neuropathy Impairment Score upper limb/lower limb ratio > 1 compared to the late-onset patient group. The study group had significantly more pronounced axonal loss in the median and ulnar motor nerves and the ulnar sensory and sural nerves. On radial nerve biopsies (n = 11), epineurial vessels were abnormal in six cases, including amyloid deposits in vessel walls (3/11), with vessel occlusion in two cases. CONCLUSION: Upper limb onset of hereditary ATTR neuropathy is not rare in non-endemic areas. It is important to propose early TTR sequencing of patients with idiopathic upper limb neuropathies, as specific management and treatment are required.

Diagnostic usefulness of plexus magnetic resonance imaging in chronic inflammatory demyelinating polyradiculopathy without electrodiagnostic criteria of demyelination.

BACKGROUND AND PURPOSE: The usefulness of plexus magnetic resonance imaging (MRI) in the diagnosis of chronic inflammatory demyelinating polyradiculopathy (CIDP) without definite European Federation of Neurological Societies/Peripheral Nerve Society (EFNS/PNS) electrodiagnostic criteria is currently unclear. METHODS: Data from consecutive patients with clinical manifestations suggesting CIDP, with or without (CIDP-D and CIDP-ND, respectively) definite EFNS/PNS electrodiagnostic criteria, and referred for plexus MRI in our imaging centre were retrospectively analysed. An expert committee of neurologists compared the level of suspicion of CIDP in CIDP-ND patients to the blinded/unblinded MRI findings. Plexus MRI was reviewed by a neuroradiologist blinded to the final diagnosis. RESULTS: In all, 38 patients were assessed with suspected CIDP-ND [7/38 (18%) probable; 13/38 (34%) possible; 18/38 (47%), no EFNS/PNS electrodiagnostic criteria], plus 10 with CIDP-D. Thirty-six of the 38 (95%) fulfilled clinical criteria of CIDP variants, including pure sensory neuropathy in 22/36 (61%). Plexus MRI showed abnormalities in 22/38 (58%) patients including increased nerve signal intensity on T2-weighted images in 22/22 (100%), nerve enlargement in 20/22 (91%) and contrast enhancement in 8/22 (36%). Plexus MRI enabled the expert committee's final diagnosis to be adjusted in 7/38 (18%) patients, and in conjunction with nerve conduction studies was a supportive criterion to classify 7/24 (29%) patients as definite CIDP. MRI abnormalities were more asymmetrical (P = 0.03) and less diffuse (P = 0.1) in CIDP-ND than in CIDP-D. CONCLUSIONS: Our observations suggest that plexus MRI makes a valuable contribution to the diagnosis of CIDP-ND patients. Further studies are needed to investigate inter-rater reliability of clinical and imaging criteria of CIDP in these patients, and the impact on outcomes.

Familial amyloid polyneuropathy: When does it stop to be asymptomatic and need a treatment?

Transthyretin familial amyloid polyneuropathy (FAP) is a rare disease with autosomal transmission due to point mutation of the transthyretin (TTR) gene. It is the most disabling hereditary neuropathy affecting sensory, motor and autonomic nerves, and is irreversible and fatal within 7 to 12 years of onset in the absence of therapy. Diagnosis is usually delayed for 1-5 years because the onset is usually insidious, and a positive family history is lacking in 50% of late-onset cases. Penetrance is variable, and depends of the age of the carrier and age of onset in family members. Two treatments are available: liver transplantation, to suppress the main source of systemic production of mutant TTR; and TTR tetramer stabilizer drugs, to avoid the release of highly amyloidogenic monomers and oligomers. These therapies are able to stop or slow the progression of the disease in its early stages. Genetic counseling is crucial to detect carriers at risk of developing the disease. The European network for TTR-FAP recommends careful baseline assessment by questionnaire, clinical examination and neurophysiological tests, and periodic consultations to detect the onset of disease in time to start anti-amyloid therapy after biopsy findings of amyloid deposition. A therapeutic educational program is important for improving patients' awareness. Patients are considered symptomatic and ill when they themselves perceive symptoms or changes, including changes from baseline measurements on neurophysiological tests, followed by findings of amyloid deposition on biopsy. The most sensitive biopsies are from the labial salivary gland and skin.

Risk factors of hematomyelia recurrence and clinical outcome in children with intradural spinal cord arteriovenous malformations.

BACKGROUND AND PURPOSE: Few published data are available concerning the risk of re-bleeding of spinal cord AVM after an hematomyelia and concerning the long-term clinical outcome. Our aim was to assess the risk of recurrence and long-term clinical outcome after hematomyelia in children with spinal cord AVMs. MATERIALS AND METHODS: This single-center retrospective study reviewed the clinical and radiologic data of 28 children younger than 18 years of age with arteriovenous malformation who had experienced at least 1 episode of hematomyelia between 1988 and 2012. Long-term clinical outcome was assessed by the American Spinal Injury Association Impairment Scale, and radiologic review included MR imaging and angioarchitecture on angiography (blinded to clinical information) before treatment and at recurrence. RESULTS: Sixteen children (57%) experienced 1 episode of hematomyelia, while 12 children (43%) experienced recurrence. Girls and boys were equally affected (sex ratio, 1:1), and mean clinical follow-up was 5.7 ± 4.4 years. The risk of recurrence was higher for AVMs of the cervical and upper thoracic spine, 12 (100%) versus 11 (69%) (P = .01). A high American Spinal Injury Association scale score at last follow-up was reported for 11 children (39%), and the risk of recurrence tended to be associated with poorer functional prognosis (7 [64%] versus 5 [29%], P = .07). At the time of recurrence, perimedullary venous drainage was the main factor associated with recurrence (P = .002). Occlusion rate ≥50% was associated with a decreased risk of recurrence (P = .047). CONCLUSIONS: In the present series, cervical and upper thoracic spinal cord AVMs and microarchitecture were predictive of the risk of hematomyelia recurrence. Perimedullary venous drainage was one of the main parameters associated with recurrence. Functional prognosis was better in patients with a single episode of hematomyelia.

[Ocular involvement in familial amyloid polyneuropathy]. / Atteintes oculaires des neuropathies amyloïdes héréditaires liées à la transthyrétine.

Familial amyloid polyneuropathy (FAP) or transthyretin (TTR) amyloid polyneuropathy is a progressive sensorimotor and autonomic neuropathy of adult onset, which is transmitted as an autosomal dominant trait. In addition to neurologic symptoms, FAP may be associated with weight loss, cardiac and renal failure and ocular complications. FAP is a devastating disease, causing death within 10years after the first symptoms. The TTR Val30Met mutation is the most common of more than 100 amyloidogenic mutations identified worldwide. Liver transplantation (LT) is currently the only treatment for preventing synthesis of the amyloidogenic variants of TTR. LT can halt progression of the neuropathy in up to 70% of cases and doubles the overall median survival of young Val30Met patients. Oral administration of tafamidis, which prevents deposition of mutated TTR, is now available to delay neurologic complications in early stages of the disease. Ocular manifestations of FAP are frequent and mainly include keratoconjunctivitis sicca, secondary glaucoma, vitreous deposits and pupillary abnormalities. Retinal and choroidal vascular abnormalities are more rare. Since ocular TTR is synthesized, at least in part, in the retinal pigment epithelium, LT does not influence the course of ocular involvement. The effects of tafamidis on the latter are still unknown. Because LT and symptomatic treatments greatly improve life expectancy of patients with FAP, ocular involvement is becoming a more frequent challenge to address. This review summarizes the pathophysiology, clinical findings and possible treatments of ocular manifestations of FAP.

Effect on disability and safety of Tafamidis in late onset of Met30 transthyretin familial amyloid polyneuropathy.

BACKGROUND AND PURPOSE: The aim of this study was to assess the effect of Tafamidis, which slows the progression of early stages of Met30 transthyretin (TTR) familial amyloidosis polyneuropathy (FAP) in more advanced cases. METHODS: The study was a prospective, non-randomized controlled trial carried out at the French national reference centre for FAP with follow-up at 1 year. Thirty-seven consecutive Met30-TTR-FAP patients were enrolled between December 2009 and July 2011, with NIS-LL (Neuropathy Impairment Score-lower limbs) > 10 and Karnofsky score > 60. Their mean (SD) age was 56.4 (19) years. Seventy-seven per cent of patients had a walking disability. Seven patients (19%) were withdrawn for adverse effects. The primary study outcome measurements, planned before data collection began, were NIS-LL and NIS-UL (upper limbs) scores and disability scores. RESULTS: Of the 37 patients entered into the study, 29 were evaluated at 6 months and 13 at 12 months. During the first 6 months of treatment, the mean progression of NIS-LL score was 4.8 and was similar to that during the period before treatment. Among the 45% of patients without NIS-LL progression, the NIS-UL score worsened in 55%. During the first year, 55% deteriorated with respect to disability and 38% with respect to NIS only; only two patients (7%) remained stable. Four (out of 20; 20%) patients who were previously stage 1 reached stage 2 (walking with aid) after this period. Two out of nine patients who were initially normotensive developed orthostatic hypotension. There were a total of 19 adverse events, including four febrile urinary tract infections and three severe diarrhoeas, with faecal incontinence in two. CONCLUSION: In most patients with advanced Met30 TTR-FAP, Tafamidis is not able to stop disease progression, in respect of both NIS-LL and disability. Other anti-amyloid medicines should be assessed in this context.

Short-term evolution of spinal cord damage in multiple sclerosis: a diffusion tensor MRI study.

INTRODUCTION: The potential of diffusion tensor imaging (DTI) to detect spinal cord abnormalities in patients with multiple sclerosis has already been demonstrated. The objective of this study was to apply DTI techniques to multiple sclerosis patients with a recently diagnosed spinal cord lesion, in order to demonstrate a correlation between variations of DTI parameters and clinical outcome, and to try to identify DTI parameters predictive of outcome. METHODS: A prospective single-centre study of patients with spinal cord relapse treated by intravenous steroid therapy was made. Patients were assessed clinically and by conventional MRI with DTI sequences at baseline and at 3 months. RESULTS: Sixteen patients were recruited. At 3 months, 12 patients were clinically improved. All but one patient had lower fractional anisotropy (FA) and apparent diffusion coefficient (ADC) values than normal subjects in either inflammatory lesions or normal-appearing spinal cord. Patients who improved at 3 months presented a significant reduction in the radial diffusivity (p = 0.05) in lesions during the follow-up period. They also had a significant reduction in the mean ADC (p = 0.002), axial diffusivity (p = 0.02), radial diffusivity (p = 0.02) and a significant increase in FA values (p = 0.02) in normal-appearing spinal cord. Patients in whom the American Spinal Injury Association sensory score improved at 3 months showed a significantly higher FA (p = 0.009) and lower radial diffusivity (p = 0.04) in inflammatory lesion at baseline compared to patients with no improvement. CONCLUSION: DTI MRI detects more extensive abnormalities than conventional T2 MRI. A less marked decrease in FA value and more marked decreased in radial diffusivity inside the inflammatory lesion were associated with better outcome.

Short and long-term effect of IVIg in demyelinating neuropathy associated with MGUS, experience of a monocentric study.

BACKGROUND: The optimal treatment for demyelinating neuropathy associated with MGUS and anti-MAG neuropathy is not known. METHODS: We retrospectively studied the efficacy of IVIg in 14 patients with DN-MGUS (seven IgM and seven IgG/A) and seven with anti-MAG neuropathies, treated in our reference center between 2002 and 2007. Patients were clinically evaluated before the first infusion, after the first infusion, and after the last IVIg treatment. RESULTS: Anti-MAG neuropathy: after a single infusion, one patient improved and six were stable. At last follow-up (mean: 15.6months [range: 3.5-31], mean number of IVIg courses: 8 [2-33]), one patient maintained her improvement from baseline. DN-MGUS: after a single infusion, nine patients improved (64%), four were stable and one deteriorated further. The factor predictive of short-term response to IVIg was relapsing neuropathy responding better in the walking score analysis (Fisher exact test: P=0.005). At last follow-up (mean: 22.6months [range 2-72], mean number of IVIg courses: seven [1-24]), neurological status improved in four patients, five patients remained stable, including three who are still under regular IVIg, and four had deteriorated. Improvement from baseline persisted for a prolonged period in two patients after IVIg were stopped. Patients who were responders on Norris after the first IVIg course were significantly better responders at long-term follow-up than the others (P=0.001). We report no serious adverse effect. CONCLUSION: IVIg are not very efficient in the management of anti-MAG neuropathies. Nevertheless, they have a frequent short-term beneficial effect in DN-MGUS, which was maintained at long-term follow-up in one-third of our patients. When a DN-MGUS patient is regularly treated by IVIg courses, frequent periodic clinical evaluations must be performed to determine when to stop treatment and switch to another one.

[New elements in the diagnosis and the treatment of primary AL amyloid polyneuropathy and neuropathy due to POEMS syndrome]. / Nouveautés dans le diagnostic et le traitement des neuropathies périphériques liées à l'amylose AL et au syndrome POEMS.

INTRODUCTION: Primary AL amyloid polyneuropathy (AL-PN) and neuropathy due to POEMS syndrome (POEMS-N) are rare, associated with a monoclonal gammopathy (MG) IgGλ or IgAλ at a low rate and systemic manifestations. They are invalidating and life-threatening. STATE OF THE ART: AL-PN usually mimics small fiber length-dependent axonal polyneuropathies, but also multifocal or painful neuropathies, POEMS-N corresponds to a rapid ascending CIDP with MG. To confirm the diagnosis of AL-PN, initial investigations should identify amyloidosis on nerve or accessory salivary glands, to establish the type of amyloid after serum free light-chain (FLC) measurements. For the diagnosis of N-POEMS, diagnosis is based on the presence of four criteria proposed by Dispenzieri. These neuropathies are associated with biomarkers, useful for diagnosis and treatment monitoring: elevated serum level of FLC monoclonal in (AL-PN) or VEGF (N-POEMS). PERSPECTIVES: Early diagnosis of these neuropathies and early treatment using high-dose melphalan associated with an autologous hematopoietic stem cell graft or low monthly doses can improve the clinical manifestations and patient survival. CONCLUSIONS: Systematic search for monoclonal gammopathy by immunofixation and serum free light chains is very useful for the management of progressive peripheral neuropathies of unknown origin.

[Acute CSF changes in the mesencephalon aqueduct after subarachnoid hemorrhage as measured by PC-MRI]. / Caractérisation des perturbations du flux de LCS dans l'aqueduc du mésencéphale par IRM-CP à la phase aiguë de l'hémorragie méningée.

PURPOSE: Determining acute intracranial hydrodynamic changes after subarachnoid hemorrhage through an analysis of the CSF stroke volume (SV) as measured by phase-contrast MRI (PC-MRI) in the mesencephalon aqueduct. METHOD: A prospective study was performed in 33 patients with subarachnoid hemorrhage. A PC-MRI imaging study was performed n the acute phase (< 48 hours). CSF flow was measured in the aqueduct. The appearance of acute hydrocephalus (HCA) was then compared with data on CSF flow, and the location of the intraventricular and perimesencephalic bleeding. RESULTS: CSF analysis was performed on 27 patients, 11 of whom presented with an acute HCA. All 11 patients had an abnormal SV in the aqueduct: patients with a communicating HCA had an increased SV (n=8); and patients with a noncommunicating HCA had a nil SV (n=3). Patients with a normal SV in the aqueduct did not develop an acute HCA. Intraventricular bleeding significantly led to HCA (P=0.02), which was of the communicating type in 70% of cases. CONCLUSION: Subarachnoid hemorrhage leads to intracranial CSF hydrodynamic modifications in the aqueduct in the majority of patients. CSF flow can help us to understand the mechanism of the appearance of acute HCA. Indeed, hydrocephalus occurred - of the communicating type in most cases - even in the presence of intraventricular bleeding.

Diagnosis and treatment of dural carotid-cavernous fistulas: a consecutive series of 27 patients.

OBJECTIVES: To report clinical characteristics, angiographical findings and results of endovascular treatment of patients presenting with dural carotid-cavernous fistulas (DCCFs). METHOD: Retrospective analysis of 27 consecutive patients with DCCF referred to a specialised interventional neuroradiology department. RESULTS: Orbital and neuro-ophthalmological symptoms were the most common clinical presentation at diagnosis (n = 25). The venous drainage of the fistula involved the ipsilateral superior ophthalmic vein in 24 patients, the contralateral cavernous sinus in 6 and a leptomeningeal vein in 5 patients. Thrombosis of at least one petrosal sinus was found in 23 patients. 7 patients did not receive endovascular treatment: 3 had spontaneous DCCF obliteration, and 4 had only minor clinical symptoms and no leptomeningeal venous drainage on an angiogram. 20 patients received endovascular treatment via either a transvenous (n = 16) or a transarterial approach (n = 4). Complete occlusion of the fistula was obtained in 14 of 16 (87%) patients treated by the transvenous approach and in 1 of 4 (25%) patients treated by the transarterial approach. 16 patients had early clinical improvement after endovascular treatment. One patient had a cerebral haemorrhage after transvenous embolisation of a DCCF with leptomeningeal drainage. On follow-up, all patients treated by the transarterial route remained symptomatic, whereas 10 of 14 (71%) patients cured by the transvenous route were asymptomatic. CONCLUSIONS: Transvenous embolisation is a safe and efficient endovascular approach to treat patients with DCCF. However, this technique requires a long learning curve.