Giuliana Galassi

Parvovirus B19 infection antedating Guillain–Barre’ syndrome variant with prominent facial diplegia

The clinical spectrum of Guillain–Barre syndrome (GBS) has expanded due to variants accounting for benign forms without progression [1–4]. Patients with acute onset of facial diplegia, with or without limb weakness, acral paraesthesias, or areflexia are affected by a regional GBS variant ‘‘facial diplegia and paraesthesias’’ (FDP) [1, 3]. This 36 year old man, 3 weeks after high fever with myalgias, experienced facial pain, difficulty in closing eyes, and pursuing lips. Taste, lacrimation, swallowing, and hearing were normal. On admission (day 2), neurological examination showed facial diplegia and areflexia. Eye movements, strength, coordination, and sensibility were unaffected. By day 4, the patient reported hand numbness. Normal laboratory tests included screening for autoimmune-rheumatic diseases. Virological, microbiological studies excluded a variety of infections (Borrelia burgdorferi, HSV-1/2, VZV, EBV, CMV, HHV-6). Serum IgG and IgM antibodies to gangliosides GM1, GM2, GM1b, GD1a, GD1b, GalNAc-GD1a, GT1a, and GQ1b were investigated (day 3) by enzyme-linked immunosorbent assay (ELISA) as described elsewhere [2, 3]. The antiganglioside antibody assays were negative. CSF (day 5) showed increased protein content (68 mg/dl, normal \ 45). ELISA revealed anti HPV-B19 IgM and IgG (titer above 5.99). Real Time PCR detected a viral load of 28,794 copies/ml. N-PCR showed HPV-B19 DNA in CSF. Electrophysiological study (day 8) showed temporally dispersed peroneal, tibial compound muscle action potentials (1.5–2 mV in amplitude, normal [ 4), border-line slowing in motor conduction (40 m/sec normal [ 45), and delayed peroneal, tibial F-waves (65 ms, normal \ 58). There were proximal conduction blocks in median and ulnar nerves [5]. Sensory fibers were spared. Brain MRI, auditory, and brain stem evoked responses were normal. Intravenous immunoglobulin was started on day 5 (IVIg 0.4 g/kg/daily) and completed over the next five days. By 3 weeks, bifacial weakness and distal numbness had recovered; on day 122, there were neither residual clinical nor electrophysiological abnormalities. ELISA (day 127) showed anti B19 IgM titer lowered to 0.79, whereas IgG remained 5.99 (Biotrin international ltd, Dublin, Ireland).Our patient presented with a post-infectious FDP variant [3]. Major features were albumino-cytologic dissociation and presence of HPV-B19 DNA in serum and CSF during the acute phase. Susuki et al. [3] reported 22 cases with a disease compatible with Ropper’s original description [1]; among those patients, marginal cases were identified without limb paraesthesias or areflexia [3]. Infection serologies during the acute phase evidenced anti-cytomegalovirus, Campylobacter jejuni, Epstein-Barr, Borrelia burgdorferi, and Mycoplasma pneumoniae IgM antibodies in 14 subjects; 13 experienced upper respiratory tract infection. Anti-ganglioside IgM antibodies were detected in five patients. Motor conduction study suggested demyelination in 14 cases and was normal in 7 [3]. HPV-B19 causes erythema infectiosum, aplastic crisis, fetal hydrops, arthritis, vasculitis, and neurological syndromes [6–9]. Skin rashes or arthralgias associated with positive rheumatoid factor and antinuclear antibodies F. Barbi A. Ariatti G. Galassi (&) Department of Neurosciences, University of Modena and Reggio Emilia, Via P. Giardini, 1350, 41010 Modena, Italy e-mail: giulianagalassi@aliceposta.it

5-Fluorouracil- and Levamisole-Associated Multifocal Leukoencephalopathy

Case Reports Case 1. A 61-year-old female, without prior neurologic history, had a resection due to colon cancer classified as Dukes stage-B2. Adjuvant chemotherapy with 5-FU (450 mg/m i.v. daily for 5 days) and levamisole (150 mg orally for 6 days) was initiated 1 month after surgery. Cycles were repeated at 4-week intervals. Ten days after the third course the patient was admitted because of confusion, dysarthria, ataxia and right hemiparesis. Meningeal signs and fever were absent. EEG was slowed bilaterally. Remote malignancies, viral, bacterial and fungal infections were ruled out. In CSF, DNA amplification for EBV, JCV, CMV and HSV was negative. MRI showed multiple, irregularly confluent, white-matter lesions, hyperintense in T2-weighted images; cerebellar hemispheres and peduncles were also affected. Chemotherapy was discontinued; dexamethasone, 12 mg i.v. daily, was given. Within a week, the patient’s conditions deteriorated to coma, with intermittent seizures, and respiratory distress. Dexamethasone was tapered over a 3month period. The patient improved, but global aphasia and quadriplegia persisted. Case 2. This previously healthy 54-year-old woman underwent a colectomy because of colon adenocarcinoma classified as Dukes stage C. After surgery, chemotherapy consisted of 5-FU (370 mg/m i.v. days 1– 5), oral levamisole (150 mg daily for 6 days) and leucovo-rin (100 mg/m i.v. for 5 days). The cycle was repeated twice at 4-week intervals. Twenty days after the second course, the patient exhibited ataxia, difficulty in naming and repetition, hyporeflexive right limb weakness, and an impaired visual field to the right. Viral, bacterial and fungal infections were excluded. EEG showed bilateral 6-activity. CSF contained 20 lymphocytes/mm, normal glucose, protein, and three oligoclonal bands. DNA amplification for JCV, HSV, EBV and CMV was negative in CSF. Gadolinium-DPTA MRI revealed T2 high-signal multiple lesions, sparing the corpus callosum (fig. la). Dexamethasone was given intravenously at 12 mg daily. Within 2 weeks, the patient’s neurologic condition improved and the steroid was tapered over 2 months. When discharged, the patient was alert and oriented, but naming and repetition were still impaired. At follow-up 2 months later, MRI lesions were less marked and confluent than previously (fig. lb), often with enhancement after gadolinium.

Prognostic factors and health-related quality of life in ocular myasthenia gravis (OMG)

We evaluate the factors predictive of prognosis in 91 Caucasian patients affected by ocular myasthenia gravis (OMG), followed at our Institution during an observational time, ranging from 12 to 240 months. The Myasthenia Gravis Foundation of America (MGFA) clinical classification was used to grade the disease severity. We considered as outcome measures the variation in two subscores, ocular (O-QMG) and nonocular (NO-QMG); the last one reflected bulbar, neck, extremity functions. None of the independent variables evaluated for association with the outcome, as age of onset, type of therapy, length of interval between first and last examinations, and presence of antibodies to acetylcholine receptors (AChR-Abs) significantly affected the evolution of O-QMG and of NO-QMG. Health-related quality of life (HRQol) was assessed in 63 patients. Variations of diplopia or ptosis did not affect significantly physical (PCS) or mental composite subscores (MCS) of the Short-Form Health Survey (SF-36). Human leukocyte antigen (HLA) genotyping was studied to explore whether HLA class I and II allelic distribution differed among MG patients and controls. None of the studied HLA alleles significantly differed between OMG patients and controls. Similarly, none of the alleles with frequencies higher than 15% either in OMG patients or in controls was significantly associated, after Bonferroni correction, with the presence or absence of anti-AChR-Abs in serum.

Long-term disability and prognostic factors in polyneuropathy associated with anti-myelin-associated glycoprotein (MAG) antibodies

Aim of the study: Neuropathy associated with IgM monoclonal gammopathy (MGUS) represents distinctive clinical syndrome, characterized by male predominance, late age of onset, slow progression, predominantly sensory symptoms, deep sensory loss, ataxia, minor motor impairment. More than 50% of patients with neuropathy-associated MGUS possess antibodies against myelin-associated glycoprotein (MAG). Purpose of our study was to assess effects on disease progression of demographic, clinical and neurophysiological variables in our large cohort of patients. Materials and Methods: Forty-three Caucasians patients were followed every eight months for median duration time of 93 months. Extremity strength was assessed with Medical Research Council (MRC) Scale, disability with overall disability status scale (ODSS), modified Rankin Scale and sensory function with Inflammatory Neuropathy Cause and Treatment (INCAT) sensory scale (ISS). Statistical analyses were conducted with parametric or non-parametric measures as appropriate. Survival analysis was used to test predictive value of clinical, demographical and neurophysiological variables. Variance analysis was conducted to explain difference on MRC between patients and groups at different time from onset. Results: Results showed that demyelinating pattern, older age and absence of treatment were significant risk factors for disability worsening. No other factors emerged as predictors including gender, ataxia and tremor at baseline, level of anti-MAG and IgM protein concentration in serum. Despite worsening of all outcome measures between first and last visit, quality of life (HRQol) judged by patients did not vary significantly. Conclusions: Our study provides evidence that electrophysiologic pattern, age of onset and absence of treatment are strong predictor of prognosis in anti-MAG polyneuropathy.

Cranial nerve involvement as presenting sign of multifocal motor neuropathy

Multifocal motor neuropathy (MMN) is characterized by slowly progressive, predominantly distal, asymmetric limb weakness and partial conduction blocks (CB) of motor axons. Cranial nerve involvement and respiratory failure are uncommon. We report two patients who exhibited unilateral hypoglossal and abducens palsy as presenting signs. Other remarkable features were autonomic instability and respiratory failure due to bilateral phrenic nerve involvement. Treatment with intravenous (IV) immunoglobulin (Ig) resulted in an improvement. Patient 2, who showed IgM reactivity against ganglioside GM1, has been receiving maintenance therapy with IVIg for 7 years. We speculate that cranial weakness of our patients could be due to CB similar to those detected in the motor nerves of the extremities.

Sensory Action Potentials and Biopsy of the Sural Nerve in the Neuropathy of Nonmalignant IgMk Plasma Cell Dyscrasia

Electrophysiological findings in 10 patients with polyneuropathy and nonmalignant IgMk plasma cell dyscrasia are reported. The amplitude of sensory action potentials and maximum conduction velocity along the sural and median nerves are related to the structural changes found at the biopsy and to the immunologic results. Quantitative analysis of the sural nerve showed a loss of large myelinated fibers in all 8 patients, in whom the nerve could be examined. The sural action potential as well as conduction velocity were undetectable in 4 cases, diminished in 5 and normal in 1. The primary mechanism underlying nerve damage in these neuropathies is discussed. It is suggested that the IgM paraprotein may act heterogeneously on the peripheral nerves component.

Factors affecting outcome in ocular myasthenia gravis

ABSTRACT Aim of the study: 50%–60% of patients with ocular myasthenia gravis (OMG) progress to generalized myasthenia gravis (GMG) within two years. The aim of our study was to explore factors affecting prognosis of OMG and to test the predictive role of several independent clinical variables. Materials and methods: We reviewed a cohort of 168 Caucasian patients followed from September 2000 to January 2016. Several independent variables were considered as prognostic factors: gender, age of onset, results on electrophysiological tests, presence and level of antibodies against acetylcholine receptors (AChR Abs), treatments, thymic abnormalities. The primary outcome was the progression to GMG and/or the presence of bulbar symptoms. Secondary outcomes were either achievement of sustained minimal manifestation status or worsening in ocular quantitative MG subscore (O-QMGS) or worsening in total QMG score (T-QMGS), assessed by Myasthenia Gravis Foundation of America (MGFA) quantitative scores. Changes in mental and physical subscores of health-related quality of life (HRQoL) were assessed with SF-36 questionnaire. Variance analysis was used to interpret the differences between AChR Ab titers at different times of follow up among the generalized and non-generalized patients. Results: Conversion to GMG occurred in 18.4% of patients; it was significantly associated with sex, later onset of disease and anti-AChR Ab positivity. Antibody titer above the mean value of 25.8 pmol/mL showed no significant effect on generalization. Sex and late onset of disease significantly affected T-QMGS worsening. None of the other independent variables significantly affected O-QMGS and HRQoL. Conclusions: Sex, later onset and anti-AChR Ab positivity were significantly associated with clinical worsening.

C10ORF2 mutation associated with progressive external ophthalmoplegia and clinically isolated syndrome

Sporadic chronic progressive external ophthalmoplegia (CPEO) is most commonly due to large-scale deletions or rearrangements of mitochondrial DNA (mtDNA) [1, 2]. MtDNA mutations are responsible for diseases involving central nervous system, for instance, Leber’s hereditary optic neuropathy (LHON), which is reported in association with both multiple sclerosis (MS) and MS-like magnetic resonance imaging (MRI) patterns, raising important questions about common pathophysiological mechanisms [1–3]. Indeed, mtDNA deletions and respiratory-deficient neurons have been described in MS [4]. Patients presenting first with clinical symptoms, not fulfilling the MRI criteria for dissemination in space and time according to the 2010 revision of the McDonald diagnostic criteria for MS, are classified as clinically isolated syndrome (CIS) possibly antedating definite MS [5]. We report the first case of mitochondrial dysfunction caused by mutation in C10ORF2 gene, presenting with CPEO associated with an incomplete transverse myelitis as CIS [5]. Case report

Coincident chronic inflammatory demyelinating polyneuropathy and focal segmental glomerulosclerosis: a common autoimmunity?

A 40-year-old male developed swallowing difficulties, loss of strength, and imbalance. On admission, the patient exhibited bifacial, extremity weakness, ataxia, impaired sensation, and areflexia. Electrophysiology and nerve biopsy suggested demyelination. Spinal fluid revealed increased protein content. Plasmapheresis showed benefit, but neuropathy relapsed. At second recurrence, urine analysis showed heavy proteinuria. Renal biopsy revealed focal segmental glomerulosclerosis (FSGS). Methylprednisolone and oral cyclophosphamide were given. Long-term steroids and immunoglobulin showed steady benefit. Concurrence of chronic inflammatory demyelinating polyneuropathy and FSGS suggests synergistic cellular and humoral autoimmune mechanisms related to either cross-reactivity within antigenic targets or mimicry between neural and renal epitopes.

Chronic inflammatory demyelinating polyradiculoneuropathy associated with inflammatory bowel diseases: questioning the autoimmunity hypothesis

Dear Editor: Inflammatory bowel diseases (IBD) are chronic disorders encompassing Crohn’s disease (CD) and ulcerative colitis (UC) characterized by abnormal mucosal immune response. Early pathology coincides with intestinal, mesenteric T-cell infiltration, cytokine production, bowel inflammation, and vasculitis. There is evidence that CD4 and CD8 T-cells can trigger autoimmunity when peripherally activated by antigens in a proinflammatory setting. Chronic inflammatory demyelinating polyradiculoneuropathies (CIDP) are caused by immune responses mounted against uncharacterized epitopes. Polyneuropathies associated with IBD exhibit different phenotypes. We studied two patients with CIDP associated with IBD supporting the view of common causality. A 63-year-old woman experienced rectal hemorrhage, acral numbness, and unsteady gait during acute hepatitis. Intestinal biopsy diagnosed CD. Neurologic examination showed absent jerks and distal loss of all sensory modalities. Muscle strength was minimally affected. Normal laboratory results included B12, E vitamin serum level, tumor markers, microbial, and immunological screenings. Sural-evoked responses were either absent or diminished in amplitude with slowed velocity. There were prolonged F wave and distal latencies of median, tibial, and peroneal muscle action potentials. Sural biopsy showed fiber loss and demyelination in 30% of fibers teased. Onion bulbs and mononuclear inflammatory cells were absent. Patient was treated with long-term steroids. On clinical follow-up, her neurological disability progressed in the absence of CD recurrence. Sixteen years after onset, distal strength was graded 3/5, whereas ataxia was marked and distal sensation was severely impaired. Electrophysiology confirmed demyelination. The second patient when aged 33 was diagnosed having UC. Twelve months later, he developed acral paresthesias and extremity weakness graded 3/5 on examination. Deep jerks were unevokable; Romberg sign was positive, and touch and deep sensation was distally impaired. In nerve conduction, there were partial motor conduction block, abnormal temporal dispersion, and diminished velocity along median, ulnar, peroneal, and tibial nerves. Patient refused spinal tap. Treatment with metronidazole was not given. Repeated courses of intravenous immuneglobulins had benefit. Our patients presented common features of moderate distal rather than proximal weakness and ataxia due to proprioceptive sensory loss. Electrophysiology suggested in both ongoing multifocal demyelination, which was histologically proven in case 1. Neurological illness began acutely in patient 1 at CD onset, raising the question of a sensory variant of acute inflammatory demyelinating polyradiculoneuropathy or of CIDP with acute onset. UC of case 2 predated by 12 months his neuropathy, which improved with immunemodulating therapy and ultimately relapsed. Gondim et al. reported seven CIDP cases associated in three with CD and in four with UC: The three CD had more proximal than distal Int J Colorectal Dis (2009) 24:603–604 DOI 10.1007/s00384-009-0646-x