Sensory neuronopathies: A case series and literature review.

Sensory neuronopathies are heterogeneous disorders of dorsal root ganglia. The clinical and laboratory features in a single-centre series, including response to treatment and outcome have been described. They retrospectively included 54 patients meeting Camdessanché et al (2009) criteria for sensory neuronopathy. The patients were classified according to their likely aetiology and analysed their demographic, clinical, neurophysiological, histological and spinal MRI features. The outcome with the modified Rankin Scale (mRS) was evaluated, and the response to treatment was assessed. About 54 patients were included (18 male; median age 54.5 years). The most common initial symptoms were hypoaesthesia, paraesthesia, ataxia and pain. Half of patients had a slow onset, greater than 12 months before seeing a neurologist. The aetiology as possibly inflammatory (meaning nonspecific laboratory evidence of immune abnormality) in 18 patients (33%), paraneoplastic 8 (15%), autoimmune 7 (13%) and idiopathic 6 (11%) was classified. About 31 patients received immune therapy of which 11 (35%) improved or stabilised. Corticosteroids were the most used treatment (24 patients) and cyclophosphamide had the highest response rate (3/6, 50%). At the final follow up (median 24 months) 67% had mRS ≥3 and 46% mRS ≥4, including 15% who died. Worse outcome was associated with generalised areflexia and pseudoathetosis by logistic regression, and with motor involvement and raised CSF protein by univariate analysis. Sensory neuronopathies caused severe disability, especially in patients with generalised areflexia and pseudoathetosis. Of those without an obvious cause, most had some evidence of dysimmunity. Some patients had a positive response to immunotherapy, but rarely enough to improve disability much.

Chronic Pharmacological Increase of Neuronal Activity Improves Sensory-Motor Dysfunction in Spinal Muscular Atrophy Mice.

Dysfunction of neuronal circuits is an important determinant of neurodegenerative diseases. Synaptic dysfunction, death, and intrinsic activity of neurons are thought to contribute to the demise of normal behavior in the disease state. However, the interplay between these major pathogenic events during disease progression is poorly understood. Spinal muscular atrophy (SMA) is a neurodegenerative disease caused by a deficiency in the ubiquitously expressed protein SMN and is characterized by motor neuron death, skeletal muscle atrophy, as well as dysfunction and loss of both central and peripheral excitatory synapses. These disease hallmarks result in an overall reduction of neuronal activity in the spinal sensory-motor circuit. Here, we show that increasing neuronal activity by chronic treatment with the FDA-approved potassium channel blocker 4-aminopyridine (4-AP) improves motor behavior in both sexes of a severe mouse model of SMA. 4-AP restores neurotransmission and number of proprioceptive synapses and neuromuscular junctions (NMJs), while having no effects on motor neuron death. In addition, 4-AP treatment with pharmacological inhibition of p53-dependent motor neuron death results in additive effects, leading to full correction of sensory-motor circuit pathology and enhanced phenotypic benefit in SMA mice. Our in vivo study reveals that 4-AP-induced increase of neuronal activity restores synaptic connectivity and function in the sensory-motor circuit to improve the SMA motor phenotype.SIGNIFICANCE STATEMENT Spinal muscular atrophy (SMA) is a neurodegenerative disease, characterized by synaptic loss, motor neuron death, and reduced neuronal activity in spinal sensory-motor circuits. However, whether these are parallel or dependent events is unclear. We show here that long-term increase of neuronal activity by the FDA-approved drug 4-aminopyridine (4-AP) rescues the number and function of central and peripheral synapses in a SMA mouse model, resulting in an improvement of the sensory-motor circuit and motor behavior. Combinatorial treatment of pharmacological inhibition of p53, which is responsible for motor neuron death and 4-AP, results in additive beneficial effects on the sensory-motor circuit in SMA. Thus, neuronal activity restores synaptic connections and improves significantly the severe SMA phenotype.

Flunarizine for Headache Prophylaxis in Children With Sturge-Weber Syndrome.

BACKGROUND: Children with Sturge-Weber syndrome can experience severe headache with or without transient hemiparesis. Flunarizine, a calcium antagonist, has been used for migraine. The experience with flunarizine for headache in a cohort of children at a national center for Sturge-Weber syndrome is reviewed, reporting its efficacy and adverse effect in this population. METHODS: We collected data from health care professionals' documentation on headache (severity, frequency, duration) before and on flunarizine in 20 children with Sturge-Weber syndrome. Adverse effects reported during flunarizine treatment were collated. The Wilcoxon signed rank test was used to determine the significance of pre- versus post-treatment effect. RESULTS: Flunarizine was used for headache alone (13) or mixed migrainous episodes and vascular events (7). The median duration of treatment was 145 days (range 43 to 1864 days). Flunarizine reduced headache severity (z = -3.354, P = 0.001), monthly frequency (z = -2.585, P = 0.01), and duration (z = -2.549, P = 0.01). Flunarizine was discontinued owing to intolerable adverse effects in a minority (2). Sedation and weight gain were the most common side effects. There were no reports of behavior change or extrapyramidal features. CONCLUSIONS: The most effective management for headaches in patients with Sturge-Weber syndrome has not been established. This retrospective observational study found benefit of flunarizine prophylaxis on headache severity, frequency, and duration in children with Sturge-Weber syndrome without severe side effects. Flunarizine is not licensed for use in the United Kingdom, but these data support its off-license specialist use for headache prophylaxis in Sturge-Weber syndrome.

Use of antiepileptic mood stabilizers in dermatology.

Several antiepileptic drugs (AEDs) are approved by the US Food and Drug Administration for the treatment of bipolar disorder (valproic acid, divalproex, lamotrigine, carbamazepine) and some cutaneous neuropathic pain syndromes (carbamazepine, gabapentin, pregabalin). The AEDs may be effective in the management of (1) chronic pruritus, including pruritus due systemic disease, including uremia, neuropathic pain, neuropathic pruritus, and complex cutaneous sensory syndromes, especially where central nervous system (CNS) sensitization plays a role; (2) management of emotional dysregulation and the resultant repetitive self-excoriation or other cutaneous self-injury in patients who repetitively stimulate or manipulate their integument to regulate emotions (prurigo nodularis, lichen simplex chronicus, skin picking disorder, trichotillomania); (3) management of dermatologic clinical manifestations associated with autonomic nervous system activation (hyperhidrosis, urticaria, flushing; these often occur in conjunction with psychiatric disorders with prominent autonomic activation and dysregulation, eg, social anxiety disorder, posttraumatic stress disorder); and (4) when certain anticonvulsants have a direct therapeutic effect (eg, in psoriasis); currently the use of AEDs for such cases is largely experimental. Gabapentin (dosage range 300-3600 mg daily) is the most widely studied AED mood stabilizer in dermatology and is especially effective in situations where CNS sensitization is a mediating factor. Further larger-scale controlled studies of AEDs in dermatology are necessary.

Inhaling xenon ameliorates l-dopa-induced dyskinesia in experimental parkinsonism.

Parkinson's disease motor symptoms are treated with levodopa, but long-term treatment leads to disabling dyskinesia. Altered synaptic transmission and maladaptive plasticity of corticostriatal glutamatergic projections play a critical role in the pathophysiology of dyskinesia. Because the noble gas xenon inhibits excitatory glutamatergic signaling, primarily through allosteric antagonism of the N-methyl-d-aspartate receptors, we aimed to test its putative antidyskinetic capabilities. We first studied the direct effect of xenon gas exposure on corticostriatal plasticity in a murine model of levodopa-induced dyskinesia We then studied the impact of xenon inhalation on behavioral dyskinetic manifestations in the gold-standard rat and primate models of PD and levodopa-induced dyskinesia. Last, we studied the effect of xenon inhalation on axial gait and posture deficits in a primate model of PD with levodopa-induced dyskinesia. This study shows that xenon gas exposure (1) normalized synaptic transmission and reversed maladaptive plasticity of corticostriatal glutamatergic projections associated with levodopa-induced dyskinesia, (2) ameliorated dyskinesia in rat and nonhuman primate models of PD and dyskinesia, and (3) improved gait performance in a nonhuman primate model of PD. These results pave the way for clinical testing of this unconventional but safe approach. © 2018 The Authors. Movement Disorders published by Wiley Periodicals, Inc. on behalf of International Parkinson and Movement Disorder Society.

Sensory neuropathic symptoms in idiopathic Parkinson's disease: prevalence and impact on quality of life.

BACKGROUND: Neuropathic symptoms are commonly reported in Parkinson's disease (PD), but robust data on the epidemiology of such symptoms are lacking. The present study sought to investigate the prevalence and determinants of peripheral sensory neuropathic symptoms (PSNS) in idiopathic PD (IPD) and ascertain the effects of such symptoms on the patients' quality of life (QoL). METHODS: Patients with IPD and age-matched and gender-matched controls were screened for neuropathic symptoms using the Michigan Neuropathy Screening Instrument. The impact of neuropathic symptoms on QoL was investigated using the 36-Item Short Form Survey. RESULTS: Fifty-two patients and 52 age-matched and gender-matched controls were recruited. PSNS were reported more frequently in patients with IPD than in the control subjects (57.7 versus 28.8%, p = 0.003). No significant relationships were found between PD-related clinical characteristics (i.e. disease severity and duration, duration of exposure to levodopa) and the presence of PSNS. Significant correlations were found between the number of PSNS and physical functioning (Spearman's Rho - 0.351), even after adjusting for age, gender and Hoehn and Yahr score. CONCLUSION: Our results support the notion of a greater prevalence of PSNS in IPD patients as compared to the general population, which, at least in part, may be secondary to large and/or small fibre peripheral neuropathy. This warrants further investigation in larger studies that include detailed neurophysiological assessments.

Exploding Head Syndrome as Aura of Migraine with Brainstem Aura: A Case Report.

This article reports a case of exploding head syndrome (EHS) as an aura of migraine with brainstem aura (MBA). A middle-aged man presented with intermittent episodes of a brief sensation of explosion in the head, visual flashing, vertigo, hearing loss, tinnitus, confusion, ataxia, dysarthria, and bilateral visual impairment followed by migraine headache. The condition was diagnosed as MBA. Explosive head sensation, sensory phenomena, and headaches improved over time with nortriptyline. This case shows that EHS can present as a primary aura symptom in patients with MBA.

Sufentanil Alleviates Intrathecal Lidocaine Induced Prolonged Sensory and Motor Impairments but not the Spinal Histological Injury in Rats.

Spinal anesthesia has evolved into a safe and widely accepted method of anesthesia. Synergy between opioids and local anesthetics further increases the quality of analgesia and decreases the dose requirement of both local anesthetics and opioids. However, over the last decades compelling evidence suggested that lidocaine could be more neurotoxic than other commonly used local anesthetics. Whether opioids can modify the local anesthetics-induced neurotoxicity is largely unexplored. Here, we investigated the effect of sufentanil on the neurotoxicity induced by intrathecal lidocaine in a rat model. Our data showed that 5 µg/ml sufentanil didn't deteriorate nor reduce the histopathological injuries induced by intrathecal application of 10% lidocaine in a rat model. However, it did alleviate sensory and motor function impairments induced by 10% lidocaine. Repeated intrathecal injection of 5 µg/ml sufentanil also decreased the paw withdraw threshold compared to the baseline. An increase in expression of activating transcription factor 3, a stress response gene, as a marker for injured neurons, was also detected in lidocaine-induced neurotoxicity, while 5 µg/ml sufentanil inhibited lidocaine-induced the upregulation of activating transcription factor 3. These results suggest that sufentanil alleviates lidocaine induced sensory and motor impairments, and did not worsen histopathological injury induced by intrathecal lidocaine.

A Randomized Trial of Oral and Transdermal Rivastigmine for Postural Instability in Parkinson Disease Dementia.

OBJECTIVES: The objective of this study was to compare the efficacy and safety of oral and transdermal rivastigmine for postural instability in patients with Parkinson disease dementia (PDD) who were candidates for a cholinesterase inhibitor. The primary outcome was the change in mean velocity of the center of pressure (CoP) after 6 months. Secondary outcomes included structural parameters of dynamic posturography, clinical rating scales, and adverse events requiring dose reduction. METHODS: Patients with PDD were randomized in a 1:1 ratio to oral or transdermal rivastigmine with target doses of 6 mg twice daily and 9.5 mg/10 cm daily, respectively. Outcomes were assessed at baseline and 6 months. Results were compared within and between groups. RESULTS: Nineteen patients completed the study (n = 8 oral, n = 11 transdermal). Mean daily doses of 9.4 (±1.5 mg) and 16.4 (±3.6 mg) were achieved in the oral and transdermal groups, respectively. The transdermal group demonstrated a significant 15.8% decrease in mean velocity of CoP (patch: P < 0.05; oral: 10.0% decrease, P = 0.16) in the most difficult scenario (eyes closed with sway-referenced support). There was no difference between groups (P = 0.27). For structural parameters, significant improvements were seen in the mean duration of peaks (patch) and interpeak distance (oral) in the most difficult condition. No changes were observed in clinical rating scales. Six patients experienced nonserious adverse events requiring dose reduction (n = 5 oral; n = 1 transdermal). CONCLUSIONS: Rivastigmine may improve certain elements of postural control, notably the mean velocity of CoP. Benefits appear to be more obvious under more taxing sensory conditions.

Could istradefylline be a treatment option for postural abnormalities in mid-stage Parkinson's disease?

BASEGROUND: Postural abnormalities are refractory complications observed in mid- to late-stage Parkinson's disease (PD). METHODS: We analyzed the effects of istradefylline, a selective adenosine A2A receptor antagonist, on posture in 21 levodopa-treated PD patients from the subanalysis of a three-month open-label study. RESULTS: The subitem score of posture (3.13) on the Movement Disorder Society revision of the Unified Parkinson's Disease Rating Scale (MDS-UPDRS) part III significantly improved following istradefylline treatment (baseline, 1.3±1.0 points vs 3months, 0.9±0.9 points; p<0.05). Among 18 patients who had postural abnormalities at baseline, defined as 1 point or greater on MDS-UPDRS part III subitem 3.13, posture improved in 9 (50%) and was unchanged in 9 (50%) patients after istradefylline treatment. Improved and unchanged groups did not show differences in baseline characteristics, except for tendency for a higher rate of Hoehn and Yahr stage IV and V (Off state) observed in the improved group. Changes in scores of posture (3.13) did not correlate with those of other MDS-UPDRS part III items, PD Questionnaire-8, PD Sleep Scale-2 and Epworth Sleepiness Scale. CONCLUSION: Based on our preliminary findings, istradefylline could be an effective treatment option for postural abnormalities in mid-stage PD patients.

The effect of perindopril on postural instability in older people with a history of falls-a randomised controlled trial.

Design: double-blind, parallel group, placebo-controlled randomised trial. Methods: we recruited people aged >65 years with at least one fall in the previous year. Participants received 4 mg perindopril or placebo daily for 15 weeks. The primary outcome was the between-group difference in force-plate measured anteroposterior (AP) sway at 15 weeks. Secondary outcomes included other measures of postural sway, limits of stability during maximal forward, right and left leaning, blood pressure, muscle strength, 6-min walk distance and falls. The primary outcome was assessed using two-way ANOVA, adjusted for baseline factors. Results: we randomised 80 participants. Mean age was 78.0 (SD 7.4) years; 60 (75%) were female. About 77/80 (96%) completed the trial. At 15 weeks there were no significant between-group differences in AP sway with eyes open (mean difference 0 mm, 95% CI -8 to 7 mm, P = 0.91) or eyes closed (mean difference 2 mm, 95% CI -7 to 12 mm, P = 0.59); no differences in other measures of postural stability, muscle strength or function. About 16/40 (42%) of patients in each group had orthostatic hypotension at follow-up. The median number (IQR) of falls was 1 (0,4) in the perindopril versus 1 (0,2) in the placebo group (P = 0.24). Conclusions: perindopril did not improve postural sway in older people at risk of falls. Clinical Trials Registration: ISRCTN58995463.

Nonmotor Effects of Conventional and Transdermal Dopaminergic Therapies in Parkinson's Disease.

Nonmotor symptoms (NMS) are an integral component of Parkinson's disease (PD). Because the burden and range of NMS are key determinants of quality of life for patients and caregivers, their management is a crucial issue in clinical practice. Although a range of NMS have a dopaminergic pathophysiological basis, this fact is underrecognized, and thus, they are often regarded as dopamine unresponsive symptoms. However, substantial evidence indicates that many NMS respond to oral and transdermal dopaminergic therapies. In contrast, certain NMS are exacerbated or even precipitated by dopaminergic drugs and these unwanted effects may be seriously dangerous. Therefore, a dopaminergic strategy for NMS should be based on a consideration of the benefits vs the risks in individual patients with PD.

Loss of cutaneous large and small fibers in naive and l-dopa-treated PD patients.

OBJECTIVE: To study small and large fiber pathology in drug-naive and l-dopa-treated patients affected by Parkinson disease (PD) in early phases, before the occurrence of neuropathic electrophysiologic abnormalities. METHODS: We enrolled 85 patients with idiopathic PD (male/female 49/36, age 61.3 ± 9.7 years) without electrophysiologic signs of neuropathy, including 48 participants naive to l-dopa treatment. All patients underwent clinical, functional, and morphologic assessment of sensory and autonomic nerves through dedicated questionnaires, quantitative sensory testing, sympathetic skin response, dynamic sweat test, and punch biopsies from glabrous and hairy skin. Sensory and autonomic innervation was visualized with specific antibodies and analyzed by confocal microscopy. Data were compared with those obtained from sex- and age-comparable healthy controls. In 35 patients, skin biopsies were performed bilaterally to evaluate side-to-side differences. RESULTS: Intraepidermal nerve fiber density was lower in patients compared to controls in all the examined sites (p < 0.001). The loss was higher in the more affected side (p < 0.01). A loss of autonomic nerves to vessels, sweat glands, and arrector pili muscles and of Meissner corpuscles and their myelinated endings in glabrous skin was found (p < 0.001). Patients showed increased tactile and thermal thresholds, impairment of mechanical pain perception, and reduced sweat output (p < 0.001). The naive and l-dopa-treated groups differed only for Meissner corpuscle density (p < 0.001). CONCLUSIONS: Both large and small fiber pathology occurs in the early stages of PD and may account for the sensory and autonomic impairment. l-Dopa affects the 2 populations of fibers differently.

Heroin-induced acute myelopathy with extreme high levels of CSF glial fibrillar acidic protein indicating a toxic effect on astrocytes.

A man aged 33 years with previous heroin substance abuse was found unconscious lying in a bush. The patient had been without heroin for some time but had just started to use intravenous heroin again, 0.5-2 g daily. The patient had almost complete paraplegia and a sensory loss for all modalities below the mamillary level and a urine retention of 1.5 L. Acute MRI of the spine revealed an expanded spinal cord with increased intramedullary signal intensity, extending from C7-T9. The cerebrospinal fluid showed extremely high levels of nerve injury markers particularly glial fibrillar acidic protein (GFAP): 2 610 000/ng/L (ref. <750). The patient was empirically treated with intravenous 1 g methylprednisolone daily for 5 days and improved markedly. Very few diseases are known to produce such high levels of GFAP, indicating a toxic effect on astrocytes. Measuring GFAP could possibly aid in the diagnosis of heroin-induced myelopathy.

Can postural abnormality really respond to levodopa in Parkinson's disease?

OBJECTIVE: Abnormal postures affect motor function in Parkinson's disease (PD), potentially compromising the quality of life. The clinical efficacy of dopaminergic medications remains uncertain. Knowing what type of abnormal posture clearly responds to dopaminergic medication would facilitate the clinical management of PD. We investigated whether abnormal posture responded to dopamine challenge testing. METHODS: We studied 24 consecutive patients with PD who had anterior trunk flexion (ATF) (n=13), antecollis (n=4), or lateral trunk flexion (LTF) (n=7). Levodopa was infused intravenously over the course of 30min. Before and after the levodopa infusion, the angle of the posture was measured with the use of "Image J" software. RESULTS: After the infusion of levodopa, the angle of the overall abnormal posture significantly decreased (p<0.001). The angle of the abnormal posture significantly decreased in both natural position (p<0.001, p=0.002) and in a position with the back averted (p=0.003, p=0.029) in patients with ATF or antecollis, but did not change significantly in patients with LTF (p=0.099). The change in the angle differed significantly between patients with ATF and those with antecollis (p=0.017) and between patients with antecollis and those with LTF (p=0.008), but did not differ significantly between patients with ATF and those with LTF (p=0.052). The change in the angle in patients with abnormal posture related to the 'off' state was significantly greater than that in patients without abnormal posture related to the 'off' state (p<0.001). CONCLUSION: Patients with LTF and some patients with ATF poorly respond to levodopa. Two phenotypes of levodopa-responsiveness exist in patients with abnormal posture, and this observation is associated with an 'off' state, especially in patients with ATF.

Continuous subcutaneous apomorphine infusion in advanced Parkinson's disease: 10-year experience with 230 patients.

Continuous apomorphine infusion (APO) is one of the treatments available for advanced Parkinson disease (PD). Over 10 years, we have treated 230 patients with APO. Mean age was 66.8 and average evolution time at APO onset was 13.0 years. Mean duration of the treatment was 26.3 months. As of June 2016, 93 remained on the medication (active group), while 137 had stopped. This active group had mean age 67.3 at recruitment and mean evolution 14.2 years. The main indication for APO was lack of deep brain stimulation criteria (DBS). Twelve patients were on waiting list for DBS. Average time since APO onset was 40.0 months. In the active group, APO decreased off-state in 4 h and allowed reducing levodopa and dopamine agonists. Dyskinesia and balance did not worsen. Cognitive decline did not change within the first 15 months. Hallucinations were the same within the first 39 months. The presence of subcutaneous nodules was the most frequent adverse event in this group. The main reason for discontinuation was side effects, being psychosis the most common. Within the first year, 82 patients stopped APO. Eighteen of these patients eventually got DBS. APO is a good option for advanced PD, since it permits a significant reduction in off-time and other antiparkinsonian drugs. This effect is sustained over time. We have treated 132 patients for over a year. Dyskinesia seems not to worsen. Combining APO with DBS simultaneously or alternatively provides good results.

Subacute autonomic and sensory neuropathy closely related to cytomegalovirus infection preceded by frequent syncopal attacks.

A 73-year-old woman who had hypertension developed a slight fever and general malaise with laboratory-proven hepatic dysfunction as well as frequent syncopal attacks 3 months before admission to our hospital. One month later, she developed urinary retention and distal limb numbness. Upon admission, her neurological examination showed reduced limb tendon reflexes, glove and stocking-type numbness, and diminished senses of touch, temperature, pain, and distal leg vibration and position. Serum cytomegalovirus (CMV) IgM antibody and CMV IgG antibody were elevated on admission, and both decreased thereafter, confirming CMV infection. No serum anti-ganglioside antibody was detected. Cerebrospinal fluid revealed a mild pleocytosis and elevated proteins. Compound muscle action potential (CMAP) amplitudes of the tibial and peroneal nerve were slightly reduced. Sensory nerve action potential (SNAP) amplitudes of the median and ulnar nerves were reduced, and sural SNAP was not evoked. Systolic blood pressure dropped 48 mmHg when the patient assumed a standing position from a supine one, demonstrating orthostatic hypotension, and a cold pressor test was abnormal, both indicating an obvious hypofunction of the sympathetic nerve. The postganglionic autonomic nerve appeared to be damaged because the accumulation of [(123)I] meta-iodobenzylguanidine was reduced on myocardial scintigraphy. These findings combined together led us to make a diagnosis of subacute autonomic and sensory neuropathy associated with CMV infection in this case. Following an eventless administration of oral fludrocortisones, intravenous immuno-globulin (IVIg) was given after one month of the hospitalization with a remarkable reduction of the syncope. This case is instructive in two points. One is that there may be a couple of months with syncope alone before the sensory disturbance appearance, and the other is that IVIg may be considerably effective for the patient-annoying syncopes. To our knowledge, this is the first report of subacute autonomic and sensory neuropathy caused by CMV infection.