Rosaria Renna

QUALITY OF LIFE AND PAIN IN PATIENTS WITH FACIOSCAPULOHUMERAL MUSCULAR DYSTROPHY

The aim of this study was to assess quality of life (QoL) and evaluate the occurrence and characteristics of pain in facioscapulohumeral muscular dystrophy (FSHD) patients. No study has yet assessed QoL in a large group of FSHD patients and, overall, few studies have assessed pain in neuromuscular diseases. We performed a prospective study using a multidimensional protocol including: clinical (according to the Clinical Severity Scale Rev1); genetic (p13E‐11 EcoRI fragments Rev1); QoL (Short Form‐36); pain (Visual Analog Scale and Portenoy‐6 questions); and depression (Beck Depression Inventory) assessment. QoL measures of FSHD were compared with those of Italian norms. Moreover, we correlated QoL and pain measurements with clinical findings. Sixty‐five patients were enrolled in the study. QoL was statistically significantly reduced with respect to the Italian normative sample, mainly in physical domains. Our study demonstrated that pain is frequent in FSHD patients. More than half of the patients complained of at least moderate pain. Women complained of slightly higher levels of deterioration in the emotional aspects of QoL than men. Clinical pattern (as assessed by Clinical Severity Scale) was closely related to physical QoL domains: the higher the clinical involvement, the more severe the QoL deterioration. This study provided information that may be crucial in clinical practice: pain may be a relevant aspect in FSHD patients, and prevention strategies or relevant therapies should be considered as appropriate. Moreover, we must pay more attention to gender differences: women can suffer far greater deterioration in the emotional aspects of QoL. Further multidimensional observations are needed. Muscle Nerve 40: 200–205, 2009

Teaching NeuroImages: Basal ganglia involvement in facio-brachial dystonic seizures associated with LGI1 antibodies

A 30-year-old man developed right faciobrachial dystonic seizures (FBDS).1 Ictal and interictal EEGs were normal. CSF analysis was unremarkable. Brain MRI revealed a gadolinium-enhancing lesion involving the left caudate and globus pallidus (figure 1). Leucine-rich glioma inactivated protein 1 (LGI1) antibodies were detected in the serum. Total-body CT scan revealed no malignancies. The patient underwent 5 cycles of plasmapheresis followed by long-term steroid therapy with complete benefit. A brain MRI performed after 5 months showed reduction of contrast enhancement (figure 2). LGI1, a secreted protein complexed with voltage-gated potassium channels, is highly expressed in the neocortex and hippocampus.2 LGI1 mutations have been described in patients with autosomal dominant partial epilepsy with auditory features (ADPEAF). Our patient had no clinical features of ADPEAF. Whether FBDS can be classified as epilepsy or dystonia is a matter of debate.3 The involvement of basal ganglia described in our patient can be relevant to the ongoing debate.

Copper deficiency myelopathy: A report of two cases

Abstract Context Copper deficiency myelopathy represents an often underdiagnosed, acquired neurological syndrome, clinically characterized by posterior column dysfunction. The main causes of copper deficiency are bariatric surgery, increased consumption of zinc, and malabsorption. However, even after a careful history taking and extensive laboratory researches, the etiology of copper deficiency remains undetermined in a significant percentage of cases. Patients affected by copper deficiency myelopathy usually present with sensory ataxia due to dorsal column dysfunction and sometimes with mild leg spasticity. In such patients, spinal cord magnetic resonance imaging (MRI) may show hyperintense lesions in T2-weighted sequences involving the posterior columns of cervical and thoracic cord. These MRI findings are not distinguishable from those of subacute combined degeneration associated with vitamin B12 deficiency. Findings Here, we describe two patients with gait ataxia and sensory symptoms in which a diagnosis of copper deficiency myelopathy was made. Both patients showed a significant clinical, neuroradiological, and neurophysiological improvement after proper supplementation therapy. Conclusion The patients herein described underline the importance to include serum copper and ceruloplasmin levels as part of the myelopathy diagnostic workup, especially in the cases of otherwise unexplained subacute myelopathy involving the posterior columns. Since copper deficiency myelopathy is a progressive syndrome, early diagnosis is mandatory in order to promptly provide a proper supplementation therapy and, thus, prevent an irreversible neurological damage.

Demyelinating and Thrombotic Diseases of the Central Nervous System: Common Pathogenic and Triggering Factors

Demyelinating diseases of the central nervous system (CNS) affect prevalently young adults and represent the main cause of neurological disability after trauma in this population (1). Multiple sclerosis (MS), acute disseminated encephalomyelitis (ADEM), and neuromyelitis optica (NMO) are the most common inflammatory-demyelinating disorders of the CNS (1, 2). Multiple sclerosis shares several features with antiphospholipid syndrome (APS) including the clinical presentation, the relapsing–remitting course, the higher incidence in females of childbearing age, and the presence of similar white matter (WM) lesions at MRI (3). Likewise, both neurological symptoms and MRI lesions may overlap in ADEM and in the initial presentation of APS (4). Therefore, MS, ADEM, and APS are part of the reciprocal differential diagnosis (2). APS represents also one of the main risk factors for cerebral venous thrombosis (CVT) (5), which is not usually included in the differential diagnosis of demyelinating diseases. However, several reports in literature have described an association between CVT and MS (6–9). Although an accurate differential diagnosis is desirable for ensuring a more targeted therapy, the examination of the shared features between thrombotic and demyelinating diseases of the CNS would help to understand their common pathogenic mechanisms.

Anti-annexin antibodies, cholesterol levels and disability in multiple sclerosis.

So far, no studies have been conducted to evaluate possible correlations between lipid/lipoprotein levels and the anti-phospholipid antibody (aPL) positivity in multiple sclerosis (MS). In this cross-sectional study, we aimed to investigate the relationships between serum lipid profile and aPL positivity rates in MS patients, and their possible differences among secondary-progressive MS (SPMS) patients, relapsing-remitting MS patients in remission (REM) and in relapse (REL). We included 16 SPMS, 58 REM and 26 REL. Their sera were tested for aPL (anti-cardiolipin, anti-β2glycoproteinI, anti-prothrombin, anti-annexinV), total cholesterol (TC), high-density lipoprotein cholesterol (HDL-C), low-density lipoprotein cholesterol (LDL-C), triglycerides (TG) and lipoprotein(a) levels. High TC levels were more frequent in SPMS patients than other groups (p=0.05). The REL had significantly higher rates of positivity for anti-β2glycoproteinI IgM (p<0.0001), anti-prothrombin IgG and IgM (both p=0.05) than the other groups. A significant positive correlation was found between age and both TC and LDL-C, disability and both TC and LDL-C, disease duration and LDL-C. TC levels were significantly higher (p=0.007) in anti-annexinV-IgG positive patients. The anti-annexinV-IgG positivity significantly associated with high levels of TC (p=0.002) and LDL-C (p=0.03). Our results support the hypothesis that both thrombogenic and neurodegenerative mechanisms associated with an abnormal cholesterol homeostasis might contribute to MS progression. Our study may have interesting practical implications, which could potentially open new therapeutic approaches in the context of appropriately designed clinical trials.

A case of CMT 1B due to Val 102/fs null mutation of the MPZ gene presenting as hyperCKemia

Charcot-Marie-Tooth disease (CMT) is a group of clinically and genetically heterogeneous neuropathies classically divided into demyelinating (CMT1) and axonal forms (CMT2). The most common demyelinating form is CMT1A, due to a duplication in the gene encoding the peripheral myelin protein 22 (PMP22). Less frequently, mutations in the myelin protein zero gene (MPZ/P0) account for demyelinating CMT1B. Herein, we report a patient presenting with an isolated hyperCKemia in whom electrophysiological and pathological findings revealed a demyelinating and axonal neuropathy. Sequencing of the MPZ gene revealed a 306delA at codon 102 in the proband and in two relatives. This mutation has been already described in association with paucisymptomatic CMT without hyperCKemia.

Concurrence of multiple sclerosis and brain tumors

Multiple sclerosis (MS) is a chronic demyelinating inflammatory disease of the central nervous system (CNS) with multi-factorial pathogenesis that includes genetic and environmental factors. A primary brain tumor is a neoplasm developing from the cells of the brain. There is high heterogeneity of primary brain tumors (about 100 different types); however, most of them develop from the glial cells. Although several types of brain tumors have been widely described in association with MS (1–20), including astrocytoma (5, 9), oligodendroglioma (12, 17), and glioblastoma (3, 11, 14, 18), it is not clear whether their occurrence is accidental or consequent to causal events. Moreover, it is not completely defined if MS and brain tumors, when associated, have a different course. The true incidence of brain tumors in MS patients is difficult to define because the diagnosis of a brain tumor in MS patients may seem more frequent than in the general population due to frequent neuroimaging scans performed in these patients (21). At the same time, pseudo-tumoral MS lesions may resemble gliomas, and conversely, early stage gliomas may resemble MS. Brain tumors in MS patients may be diagnosed later or even post-mortem (22), especially in patients with progressive MS, since the new symptoms may be attributed to the gradual clinical progression of MS rather than to the slow growing of tumor itself (23). A recent study reported that MS patients have a decreased overall cancer risk, but an increased risk for brain tumor (24). If immunosuppressive treatment for MS might promote cancerogenesis is still matter of debate, it is difficult to explain on this basis why MS patients have a decreased overall cancer risk and an increased risk only for brain and genitourinary tract tumors (24). A successive systematic analysis showed no increased or decreased risks for glioma in MS patients, while an increased risk was found for meningioma, as a result of incidental findings (25). Moreover, several autoimmune diseases influence negatively the survival in glioma and meningioma, likely due to pre-existent disability or treatment limitations (25).

Antiphospholipid antibodies: a possible biomarker of disease activity in multiple sclerosis and neuromyelitis optica spectrum disorders

Multiple sclerosis (MS) and neuromyelitis optica spectrum disorders (NMOSD) are chronic inflammatory demyelinating disease of the central nervous system. MS usually begins with a relapsing-remitting course manifesting with relapses followed by recovery. Most patients will enter a secondary progressive phase characterized by steady accumulation of disability. NMOSD is a more severe disorder characterized by optic neuritis, longitudinally extensive myelitis and autoantibody positivity against the water channel aquaporin-4. It has been demonstrated that reactivity for different autoantibodies, including antinuclear and antiphospholipid antibodies (aPL), is more frequent in NMOSD compared to MS [1, 2]. Iong and colleagues [1] have confirmed a significantly higher positive rate for anticardiolipin antibodies (aCL) in NMOSD (45.7 %) compared to MS (5.6 %). We found a similar aCL positivity (5 %) in MS patients, although the overall aPL positive rate increased up to 60 % when the reactivity for more aPL was evaluated [3]. Based on the literature data, it appears that the rate of aPL positivity in MS is related to both the number of antibodies used and the severity of the disease stage [3–6]. Indeed, aPL positivity was reported to be higher in secondary progressive than in relapsing-remitting phase [4, 5], and to be correlated with the T2-lesion volume at MRI [5]. Moreover, aPL positive relapsing-remitting MS patients developed more severe clinical and MRI disease progression compared to aPL negative ones over a 3-year follow-up [7]. Nevertheless, the highest rate of aPL positivity (about 80 %) was found only during MS relapse [3, 4, 6] correlating with the number of MRI enhancing lesions [6]. Interestingly, aPL positivity significantly decreased in the same patients in remission [3, 4]. Iong’s paper [1] has reported a similar trend also in NMOSD: patients positive for both IgG and IgM aCL were older and with a higher level of disability compared to patients positive only for IgG aCL who were, in turn, older than aCL negative patients. Moreover, aCL positivity in NMOSD patients has been associated with greater antithrombin-III activity and D-dimer levels, a product of fibrin degradation, thus confirming the association of aCL with thrombotic processes. To our knowledge, only few studies have evaluated coagulation factors in MS [8–13], generally confirming the activation of the coagulation cascade. However, the presence of thrombotic processes in MS has been well-recognized [14]. Since aPL are found not only in antiphospholipid syndrome (APS), NMOSD and MS, but also in many inflammatory diseases and infections, it is reasonable to suppose that they may be a nonspecific biomarker of underlying universal inflammatory-thrombotic events. Thus, aPL may reflect the intensity of these pathological processes i.e. the disease severity/activity rather than its specificity. In fact, another study, based on patients’ positivity for anti-b2glycoprotein-I, has classified the different types of MRI cerebral lesions in: typical inflammatory, typical vascular and the most common atypical lesions, proposed by the authors as a frontier syndrome between APS and MS [15]. This could also mean that aPL are prevalently involved in the clearance of damaged molecular and cellular components containing phospholipids rather than triggering the disease. Therefore, the higher aPL reactivity rate in T. Koudriavtseva (&) D. Plantone R. Renna Multiple Sclerosis Center, Unit of Neurology, Regina Elena National Cancer Institute, IFO, Via Elio Chianesi 53, 00144 Rome, Italy e-mail: tatiana.koud@gmail.com; koudriavtseva@ifo.it

Brain perfusion by arterial spin labeling MRI in multiple sclerosis.

The role of MRI in multiple sclerosis (MS) has been well established for decades. Moreover, new MRI techniques have been developed to better understand the complex pathogenesis of this disease, since the use of conventional MRI techniques is partially limited by its weak associations with clinical features and low sensitivity for gray matter (GM) involvement and diffuse damage of white matter (WM) [1]. These limitations become even more significant in the disease shift from the predominantly inflammatory to degenerative phase [1]. MS has been traditionally considered a demyelinating inflammatory disorder of the central nervous system; however, vascular involvement and perfusion abnormalities are recently receiving an increasing interest [2]. Earlier PET and SPECT studies showed metabolic alterations and perfusion deficits in cognitively impaired MS patients, particularly at the cortical level in the left frontal and temporal lobes [3]. Recently, a dynamic susceptibility contrast-enhanced (DSC) MRI showed in MS a globally reduced but regionally mixed cerebral blood flow (CBF). Decreased CBF has been demonstrated in both normalappearing WM (NAWM) [4–7] and deep GM [6, 7] in relapsing–remitting MS (RRMS) patients, which had also a significantly reduced CBF in the putamen compared to patients with clinically isolated syndrome (CIS) [7]. Interestingly, the greater reduction of NAWM CBF was found in primary-progressive MS compared to RRMS [5, 6], though NAWM CBF was decreased even in CIS patients [7]. A regional increase of CBF has been detected in early lesion stages, up to 3 weeks prior to brain–blood barrier (BBB) breakdown with subsequent contrast enhancement [8]. Furthermore, NAWM CBF was shown to significantly correlate with clinical disability [5], whereas GM CBF correlated with neuropsychological dysfunctions [6]. Due to recent increasing availability of higher field strength scanners, a new MRI technique called arterial spin labeling (ASL) has been proposed as a useful research tool in several neurological diseases. Interestingly, a reduction of GM CBF measured by ASL was confirmed in all MS patients compared to healthy controls while NAWM CBF has been alternatively found decreased in some studies [9– 11], or increased in others [12, 13]. The reason for the increased NAWM CBF in few studies could be the incomplete separation between NAWM and both WM and enhanced lesions due to the relatively coarse resolution of ASL and non-use of exogenous contrast. Most T1-hypointense lesions were concentrated in WM regions with lower CBF, whilst the T2-hyperintense lesions were distributed in WM regions with both higher and lower CBF [11]. The negative correlations between the T2-hyperintense lesion volume and regional CBF have been showed in several brain areas [14]. Moreover, cerebral vasoreactivity (CVR) from normocapnic to hypercapnic CBF was found diminished in MS patients compared to healthy controls indicating an impaired CBF regulation [15]. Since decreased GM CVR correlated positively with GM atrophy and negatively with the lesion volume, it was hypothesized that the impaired CBF regulation may cause neurodegeneration due to an insufficient blood supply [15]. Similar to & Tatiana Koudriavtseva tatiana.koud@gmail.com

Ultrasound study shows nerve atrophy in post herpetic neuralgia

Herpes zoster (HZ), or shingles, caused by reactivation of the atent varicella zoster virus (VZV) in the dorsal root or trigeminal anglia, is most common after the sixth decade of life. It usually resents as a unilateral dermatomal vesicular rash, associated with evere pain. Painful rash eruption is usually localized to the thoacic nerves or to the ophthalmic division of the trigeminal nerve istribution. VZV usually persists asymptomatic in the sensory ganlia of anyone who has suffered from chickenpox. It reactivates in bout 25% of people to travel along the sensory nerve fibers causing esicular lesions in the dermatome supplied by the nerve. One of he most common and debilitating sequelae of HZ is post herpetic euralgia (PHN), defined as pain persisting more than 3 months fter the rash has healed. PHN is one of the most common causes f severe neuropathic pain. The diagnosis of both HZ and PHN is sually made clinically on the basis of the characteristic rash and atient’s symptoms. We report the results of an ultrasonographic tudy of a patient with L5-S1 ganglionopathy due to VZV reactivaion, followed by PHN.