FDXR-associated disease: a challenging differential diagnosis with inflammatory peripheral neuropathy.

BACKGROUND AND AIMS: Mutations in FDXR gene, involved in mitochondrial pathway, cause a rare recessive neurological disorder with variable severity of phenotypes. The most common presentation includes optic and/or auditory neuropathy, variably associated to developmental delay or regression, global hypotonia, pyramidal, cerebellar signs, and seizures. The review of clinical findings in previously described cases from literature reveals also a significant incidence of sensorimotor peripheral polyneuropathy (22.72%) and ataxia (43.18%). To date, 44 patients with FDXR mutations have been reported. We describe here on two new patients, siblings, who presented with a quite different phenotype compared to previously described patients. METHODS: Clinical, neurophysiological, and genetic features of two siblings and a systematic literature review focused on the clinical spectrum of the disease are described. RESULTS: Both patients presented with an acute-sub-acute onset of peripheral neuropathy and only in later stages of the disease developed the typical features of FDXR-associated disease. INTERPRETATION: The peculiar clinical presentation at onset and the evolution of the disease in our patients and in some cases revised from the literature shed lights on a new possible phenotype of FDXR-associated disease: a peripheral neuropathy which can mimic an acute inflammatory disease.

Diagnostic and therapeutic recommendations in adult dystonia: a joint document by the Italian Society of Neurology, the Italian Academy for the Study of Parkinson's Disease and Movement Disorders, and the Italian Network on Botulinum Toxin.

The diagnostic framework and the therapeutic management of patients with adult dystonia can represent a challenge for clinical neurologists. The objective of the present paper is to delineate diagnostic and therapeutic recommendations for dystonia provided by a panel of Italian experts afferent to the Italian Society of Neurology, the Italian Academy for the Study of Parkinson's Disease and Movement Disorders, and the Italian Network on Botulinum Toxin. We first discuss the clinical approach and the instrumental assessment useful for diagnostic purpose. Then, we analyze the pharmacological, surgical, and rehabilitative therapeutic options for adult dystonia. Finally, we propose a hospital-territory network model for adult dystonia management.

Guillain-Barré syndrome and COVID-19: A 1-year observational multicenter study.

BACKGROUND AND PURPOSE: Many single cases and small series of Guillain-Barré syndrome (GBS) associated with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection were reported during the coronavirus disease 19 (COVID-19) outbreak worldwide. However, the debate regarding the possible role of infection in causing GBS is still ongoing. This multicenter study aimed to evaluate epidemiological and clinical findings of GBS diagnosed during the COVID-19 pandemic in northeastern Italy in order to further investigate the possible association between GBS and COVID-19. METHODS: Guillain-Barré syndrome cases diagnosed in 14 referral hospitals from northern Italy between March 2020 and March 2021 were collected and divided into COVID-19-positive and COVID-19-negative. As a control population, GBS patients diagnosed in the same hospitals from January 2019 to February 2020 were considered. RESULTS: The estimated incidence of GBS in 2020 was 1.41 cases per 100,000 persons/year (95% confidence interval 1.18-1.68) versus 0.89 cases per 100,000 persons/year (95% confidence interval 0.71-1.11) in 2019. The cumulative incidence of GBS increased by 59% in the period March 2020-March 2021 and, most importantly, COVID-19-positive GBS patients represented about 50% of the total GBS cases with most of them occurring during the two first pandemic waves in spring and autumn 2020. COVID-19-negative GBS cases from March 2020 to March 2021 declined by 22% compared to February 2019-February 2020. CONCLUSIONS: Other than showing an increase of GBS in northern Italy in the "COVID-19 era" compared to the previous year, this study emphasizes how GBS cases related to COVID-19 represent a significant part of the total, thus suggesting a relation between COVID-19 and GBS.

Case Report: A Fatal Case of West Nile Virus Meningoencephalomyelitis in a Woman with Systemic Lupus Erythematosus Initially Misdiagnosed as SARS-CoV-2 Infection.

We present a fatal case of West Nile virus meningoencephalomyelitis initially misdiagnosed as COVID-19 in a 63-year-old Egyptian woman with a previous diagnosis of systemic lupus erythematosus. The patient's medical history and immunosuppressive therapy, as well as the COVID-19 pandemic, substantially broadened the differential diagnosis of her encephalitis.

Inspiratory Vocal Fry: Anatomical and Physiological Aspects, Application in Speech Therapy, Vocal Pedagogy and Singing. A Pilot study.

OBJECTIVE: Inspiratory Vocal Fry (IVF) is the voice production during inspiration of a sound with vocal fry perceptual characteristics. The existing scientific literature shows a lack of studies on it. The aim of the study is to highlight anatomical and physiological characteristics of IVF, to assess its effects on spoken and singing voice, to confirm the potential usefulness in speech therapy and vocal pedagogy. METHODS: Thirty-two healthy subjects (17 male and 15 female) underwent videolaryngostroboscopy to assess the degree of false vocal folds adduction, pharyngeal wall contraction, and degree of vocal folds stretching in different types of phonation: expiratory and inspiratory phonation, Expiratory Vocal Fry (EVF) and IVF. All these parameters were evaluated by a group of three speech therapists and one phoniatrician not belonging to the research group. In addition, for each subject an electroglottography was performed for all the types of phonation previously mentioned, highlighting Contact Quotient (CQ) and Closing/Closed Quotient (CCQ). Three subjects underwent electromyography for a preliminary study of the muscle activation in IVF. RESULTS: False vocal folds adduction (P value = 0.000005) and pharyngeal wall contraction (P value = 0.001155) were significantly reduced in IVF compared to EVF; on the contrary, vocal folds stretching was significantly higher in IVF (P value = 0.000031). Electroglottographic CQ was significantly higher in IVF compared to EVF (P value = 0.019592) and the other types of phonation. Similar results were obtained considering CCQ, as IVF values for this parameter was significantly higher compared to EVF (P value = 0.013062) and expiratory phonation (P value = 0.001324). As regards electromyography, medial thyroarytenoid (TA) motor units were more recruited in IVF, while lateral TA motor units were more recruited in EVF. According to our results, IVF is characterized by higher elastic tension due to a reduced hypertonic contraction of TA muscle and a higher contraction of cricothyroid muscle. Electroglottographic results showed a wider vibratory cycle with an improved massaging effect on vocal folds mucosa. electromyography preliminary analysis confirmed our findings. CONCLUSION: IVF could be an excellent and useful exercise to reduce muscular hypertonic tension and to facilitate mucosal elasticity. It could be potentially applied in speech therapy approach to dysfunctional and organic dysphonias, post-surgical treatment, in pedagogy and practice of artistic voice.

Guillain-Barré syndrome and COVID-19: an observational multicentre study from two Italian hotspot regions.

OBJECTIVE: Single cases and small series of Guillain-Barré syndrome (GBS) have been reported during the SARS-CoV-2 outbreak worldwide. We evaluated incidence and clinical features of GBS in a cohort of patients from two regions of northern Italy with the highest number of patients with COVID-19. METHODS: GBS cases diagnosed in 12 referral hospitals from Lombardy and Veneto in March and April 2020 were retrospectively collected. As a control population, GBS diagnosed in March and April 2019 in the same hospitals were considered. RESULTS: Incidence of GBS in March and April 2020 was 0.202/100 000/month (estimated rate 2.43/100 000/year) vs 0.077/100 000/month (estimated rate 0.93/100 000/year) in the same months of 2019 with a 2.6-fold increase. Estimated incidence of GBS in COVID-19-positive patients was 47.9/100 000 and in the COVID-19-positive hospitalised patients was 236/100 000. COVID-19-positive patients with GBS, when compared with COVID-19-negative subjects, showed lower MRC sum score (26.3±18.3 vs 41.4±14.8, p=0.006), higher frequency of demyelinating subtype (76.6% vs 35.3%, p=0.011), more frequent low blood pressure (50% vs 11.8%, p=0.017) and higher rate of admission to intensive care unit (66.6% vs 17.6%, p=0.002). CONCLUSIONS: This study shows an increased incidence of GBS during the COVID-19 outbreak in northern Italy, supporting a pathogenic link. COVID-19-associated GBS is predominantly demyelinating and seems to be more severe than non-COVID-19 GBS, although it is likely that in some patients the systemic impairment due to COVID-19 might have contributed to the severity of the whole clinical picture.

Respiratory dysfunction as first presentation of myasthenia gravis misdiagnosed as COVID-19.

BACKGROUND: The outbreak of the coronavirus disease 2019 (COVID-19) has had profound impact on health care not only for its direct effects, but also because it deeply influenced the whole clinical practice and diagnostic pathways, particularly in the acute setting. CASE REPORT: We present the case of a patient with respiratory dysfunction due to myasthenia gravis (MG) initially misdiagnosed as severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection due to ambiguity in the interpretation of radiological and microbiological findings during COVID-19 pandemic. DISCUSSION: Respiratory dysfunction as first clinical manifestation of myasthenia gravis is rare, but potentially very harmful. Emergency physicians should always consider neurological diseases when dyspnea cannot be explained by cardiac or respiratory causes.

Diagnosing herpes simplex-1 encephalitis at the time of COVID-19 pandemic.

CASE REPORT: We describe the case of a 73-year-old woman who was diagnosed with herpes simplex virus-1 encephalitis during the COVID-19 pandemic. The diagnosis was somehow delayed because relatives were initially cautious in bringing the patient to the hospital and, here, the work-up focus was on coronavirusrelated aspects as the patient was initially reputed to be infected with COVID-19. CONCLUSIONS: During the current viral outbreak, physicians should not neglect the possibility of other diseases that represent neurological emergencies and require immediate recognition and treatment.

Acetyl-L-carnitine: from a biological curiosity to a drug for the peripheral nervous system and beyond.

Acetyl-L-carnitine (ALC) is a molecule derived from acetylation of carnitine in the mitochondria. Carnitine acetylation enables the function of CoA and facilitates elimination of oxidative products. Beyond this metabolic activity, ALC provides acetyl groups for acetylcholine synthesis, exerts a cholinergic effect and optimizes the balance of energy processes. Acetylcarnitine supplementation induces neuroprotective, neurotrophic and analgesic effects in the peripheral nervous system. In the recent studies, ALC, by acting as a donor of acetyl groups to NF-kb p65/RelA, enhanced the transcription of the GRM2 gene encoding the mGLU2 receptors, inducing long-term upregulation of the mGluR2, evidencing therefore that its long-term analgesic effects are dependent on epigenetic modifications. Several studies, including double-blind, placebo-controlled, parallel group studies and few open studies showed the effect of ALC in diseases characterized by neuropathies and neuropathic pain: the studies included diabetic neuropathy, HIV and antiretroviral therapy-induced neuropathies, neuropathies due to compression and chemotherapeutic agents. Double-blinded studies involved 1773 patients. Statistical evaluations evidenced reduction of pain, improvements of nerve function and trophism. In conclusion, ALC represents a consistent therapeutic option for peripheral neuropathies, and its complex effects, neurotrophic and analgesic, based on epigenetic mechanism, open new pathways in the study of peripheral nerve disease management.

Botulinum neurotoxin-A does not spread to distant muscles after intragastric injection: A double-blind single-fiber electromyography study.

The purpose of this study was to perform a careful neurophysiological examination to identify subclinical signs of botulinum toxin spread distant to the injection site following intragastric injection for obesity treatment. Single-fiber electromyography of extensor digitorum communis and repetitive stimulation of abductor digiti minimi were performed before and 8 days after multiple intragastric injections of botulinum toxin A (Botox, 200 U per patient) or placebo. The study was performed in a randomized double-blind fashion. No patient in either group displayed results indicative of neuromuscular dysfunction either before or after the treatment. No significant change in muscle jitter was observed when comparing baseline with the after-treatment evaluation in either group, and no significant differences between groups were observed. After intragastric botulinum toxin injection no subclinical sign of distant spread was observed.

Defective Fas-mediated T-cell apoptosis predicts acute onset CIDP.

Guillain-Barré syndrome (GBS) and chronic inflammatory demyelinating polyneuropathy (CIDP) are immune-mediated neuropathies. GBS is characterized by acute onset and subsequent remission of symptoms, whereas CIDP displays slow progression over at least 2 months. However, a small proportion of CIDP patients display acute onset CIDP (a-CIDP) resembling that of GBS. The Fas receptor is involved in shutting off the immune response and its defective function predisposes to auto-immune diseases. In CIDP patients, Fas function is lower than in GBS patients and healthy controls. This study is aimed at assessing whether evaluation of T-cell Fas function helps in early discrimination between GBS and a-CIDP. Fas function was evaluated in patients with acute onset polyneuropathy: 55 retrospective patients analyzed after development of GBS or a-CIDP before year 2005; 50 prospective patients analyzed at onset after year 2005 and followed up for development of GBS or a-CIDP. In both groups, a-CIDP patients displayed defective Fas function, whereas GBS patients displayed normal function. These findings suggest that the evaluation of Fas function in acute onset polyneuropathy helps in early prediction of long-term outcome.

Horner's syndrome as a complication of thyroidectomy: report of a case.

We report a case of Horner's syndrome (HS) occurring as a complication after total thyroidectomy. Horner's syndrome is characterized by myosis, eyelid ptosis, enophthalmos, and lack of sweating, with vascular dilatation of the lateral part of the face, caused by damage of the cervical sympathetic chain. We found only 28 other reports of HS developing after thyroidectomy, and only seven of these patients recovered completely. Of the 495 thyroidectomies performed at our hospital between 1997 and 2007, only one (0.2%) was complicated by the development of HS. The patient was a 35-year-old woman who underwent total thyroidectomy for Basedow-Graves' disease. Horner's syndrome manifested on postoperative day 2, but without anhydrosis or vascular dilatation of the face, and the symptoms resolved spontaneously 3 days later. The possible causes of HS after thyroidectomy include postoperative hematoma, ischemia-induced neural damage, and stretching of the cervical sympathetic chain by the retractor. The prompt and complete recovery of this patient suggests that the cervical sympathetic chain was damaged by retractor stretching.

Botulinum toxin therapy: a tempting tool in the management of salivary secretory disorders.

PURPOSE: The aim of the study was to investigate the feasibility and effectiveness of botulinum toxin therapy in salivary secretory disorders. MATERIALS AND METHODS: We treated 24 patients with botulinum neurotoxin type A for drooling, salivary fistulas, sialoceles, recurrent parotitis, and Frey's syndrome; each parotid gland and submandibular gland received 25 to 60 and 10 to 40 mouse units, respectively, per session. All the patients other than those with Frey's syndrome underwent, for diagnostic purpose, color Doppler ultrasonography (Hitachi H 21; frequency, 7.5 MHz, Scanner, Kashiwa, Japan), and Minor's test was carried out for gustatory sweating; pretreatment magnetic resonance sialography (Philips Gyroscan Intera, Eindhoven, The Netherlands) and sialoendoscopy were also performed in selected cases. The follow-up included clinical and ultrasonographic examinations and Minor's test. RESULTS: A clinical improvement was observed in all patients: complete clinical recovery in 12, subtotal in 6, and partial in 6. A self-assessment test suggested the cessation of sweating by the 10th day in most patients with Frey's syndrome. Botulinum toxin lost its effectiveness approximately after 4 months, requiring further administrations especially for drooling. No major side effects were observed with the exception of transitory paresis of the lower branch of the facial nerve in a patient with concomitant autonomic diabetic neuropathy. CONCLUSIONS: Our findings suggest that botulinum toxin therapy is valid for the nonsurgical management of patients with salivary secretory disorders; the use of color Doppler ultrasonographic monitoring warrants the safety of the procedure.

Overview on pathophysiology and newer approaches to treatment of peripheral neuropathies.

Peripheral neuropathies are extremely heterogeneous nosological entities. One of the most common symptoms is pain, the underlying mechanisms of which are numerous and complex. Inflammation, reparative processes, and anatomical and gene expression alterations lead to chronic pain, the persistence of which is sustained by peripheral and central sensitisation mechanisms. Treatment of peripheral neuropathies is targeted to its symptomatic and aetiological features. For pain relief, several types of drugs may be used, notably antidepressants (e.g. tricyclic antidepressants, selective serotonin reuptake inhibitors, and both serotonin and noradrenaline [norepinephrine] reuptake inhibitors), antiepileptic drugs (e.g. carbamazepine, phenytoin, lamotrigine, valproic acid, gabapentin, topiramate and pregabalin), NSAIDs and opioid analgesics. Aetiological therapy is aimed at modifying the pathophysiological mechanisms underlying the neuropathy, some of which are common in different neuropathic conditions. Certain drugs are known to exert more than one action on different pathophysiological mechanisms. This is the case with acetyl-L-carnitine (ALC), which can be considered both a symptomatic therapy that can be used in any kind of painful neuropathy, and an aetiological therapy, at least in diabetic neuropathy and neuropathies induced by nucleoside reverse transcriptase inhibitors and cancer chemotherapeutic agents. ALC acts via several mechanisms, inducing regeneration of injured nerve fibres, reducing oxidative stress, supporting DNA synthesis in mitochondria, and enhancing nerve growth factor concentrations in neurons.

Fas-mediated T-cell apoptosis is impaired in patients with chronic inflammatory demyelinating polyneuropathy.

The Fas death receptor is expressed by activated lymphocytes and is involved in switching-off the immune response. Its inherited defects cause auto-immune lymphoproliferative syndrome. Impaired Fas function may also play a role in other auto-immune diseases, such as multiple sclerosis and type 1 diabetes mellitus. The aim of this work was to evaluate Fas function in T cells from patients with chronic inflammatory demyelinating polyneuropathy (CIDP). We evaluated Fas-induced apoptosis in T-cell lines from 27 patients with CIDP, 12 patients with acute inflammatory demyelinating polyneuropathy (AIDP), and 110 controls. CIDP patients displayed lower Fas function than both AIDP patients and controls, whereas no statistically significant difference was found between AIDP patients and controls. Moreover, Fas function was lower in CIDP patients with progressive course than in those with relapsing-remitting course and lower in CIDP patients with axonal damage than in those with pure demyelination. These data suggest that defective Fas function favours CIDP development and aggressive evolution.