Impairment of brain and muscle energy metabolism detected by magnetic resonance spectroscopy in hereditary spastic paraparesis type 28 patients with DDHD1 mutations

Mutations in DDHD1 gene have been associated with the SPG28 subtype of Hereditary Spastic Paraparesis (HSP). Clinical phenotype includes axonal neuropathy, distal sensory loss, and cerebellar eye movement disturbances. We screened 96 index subjects from recessive HSP families for mutation and identified one family with two sibs carrying mutations in DDHD1 gene. Clinical, neuropsychological, and neuroimaging studies were performed, including MR spectroscopy of brain and muscle of the two mutated patients. Two novel heterozygous mutations in DDHD1 were found in the affected members of one family, with clinical features overlapping the SPG28 subtype. Of note, MR spectroscopy of brain and muscle in these patients indicated a mild deficit of brain energy metabolism in the oldest and most severely affected patient, while an impairment of energy metabolism was found in the skeletal muscle of both patients. Unlike the DDHD2 mutated patients, no evidence of lipid accumulation in the brain was found. Our data along with those previously reported suggest a dysfunction in the OXPHOS system possibly due to mitochondrial lipid content modification, which could be a central mechanism in the pathogenesis of SPG28

Immune or genetic-mediated disruption of CASPR2 causes pain hypersensitivity due to enhanced primary afferent excitability

Human autoantibodies to contactin-associated protein-like 2 (CASPR2) are often associated with neuropathic pain, and CASPR2 mutations have been linked to autism spectrum disorders, in which sensory dysfunction is increasingly recognized. Human CASPR2 autoantibodies, when injected into mice, were peripherally restricted and resulted in mechanical pain-related hypersensitivity in the absence of neural injury. We therefore investigated the mechanism by which CASPR2 modulates nociceptive function. Mice lacking CASPR2 (Cntnap2(-/-)) demonstrated enhanced pain-related hypersensitivity to noxious mechanical stimuli, heat, and algogens. Both primary afferent excitability and subsequent nociceptive transmission within the dorsal horn were increased in Cntnap2(-/-) mice. Either immune or genetic-mediated ablation of CASPR2 enhanced the excitability of DRG neurons in a cell-autonomous fashion through regulation of Kv1 channel expression at the soma membrane. This is the first example of passive transfer of an autoimmune peripheral neuropathic pain disorder and demonstrates that CASPR2 has a key role in regulating cell-intrinsic dorsal root ganglion (DRG) neuron excitability

An inflammatory myopathy unmasks a case of leprosy in an Italian patient

N.A

Non-paraneoplastic ataxia in a patient with contactin-associated protein-2 antibodies and benign course

N.A

Combined brain positron emission tomography/magnetic resonance imaging in GABAA receptor encephalitis

N

Muscle and skin sympathetic activities in Ross syndrome

Objectives: Ross syndrome (RS) is a rare degenerative disorder characterized by tonic pupil, areflexia and anhydrosis. The underlying lesion affects postganglionic skin sympathetic nerve fibers whereas the postganglionic muscle sympathetic branch is thought to be spared. Microneurography explores both skin and muscle peripheral sympathetic branches and it does not usually detect peripheral sympathetic outflow in either branch in chronic autonomic failure syndromes. The aim of this study was to record sympathetic activity by microneurography for the first time in RS patients to confirm the selective involvement of skin sympathetic nerve activity (SSNA) with spared muscle sympathetic nerve activity (MSNA). Methods: We studied seven patients (49 \ub1 14 years, four males) with a typical clinical picture and skin biopsy findings. Patients underwent cardiovascular reflexes and microneurography from the peroneal nerve (anhydrotic skin) to record MSNA, SSNA and the corresponding organ effector responses (skin sympathetic response-SSR and skin vasomotor response-SVR) in the same innervation field. The absence of sympathetic bursts was established after exploring at least three different corresponding nerve fascicles. Twenty age-matched healthy subjects served as controls. Results: RS patients complained of diffuse anhydrosis and they showed tonic pupil and areflexia. Cardiovascular reflexes were normal. All patients displayed absent SSNA, SSR and SVR whereas MSNA was always recorded showing normal characteristics. Conclusion: Microneurographic study of sympathetic activity from affected skin confirmed the selective involvement of skin sympathetic activity with spared muscle sympathetic activity and it may represent the neurophysiological hallmark of the disease. Significance: Microneurography together with clinical and skin biopsy findings may contribute to RS diagnosis. Our data also suggest that autonomic damage in RS does not involve cardiovascular activity

Comparison of ice pack test and single-fiber EMG diagnostic accuracy in patients referred for myasthenic ptosis

OBJECTIVE: To compare the diagnostic accuracy of ice pack test (IPT) and single-fiber EMG (SF-EMG) in patients with suspected ocular myasthenia (OM) presenting with ptosis. METHODS: We studied consecutive patients referred for the clinical suspicion of OM. Patients underwent IPT and stimulated SF-EMG on the orbicularis oculi muscle. Receiver operating characteristic curve analysis was performed to determine the accuracy of IPT, SF-EMG, and their combination. RESULTS: We included 155 patients, 102 with OM and 53 with other diagnosis (OD). The IPT had a sensitivity of 86% (95% confidence interval [CI] 79-93) and a specificity of 79% (95% CI 68-90). SF-EMG showed a sensitivity of 94% (95% CI 89-98) and a specificity of 79% (95% CI 68-90). Overall, IPT and SF-EMG showed discordant results in 30 cases, 16 OM and 14 OD. The combination of IPT and SF-EMG, using the positivity of at least one test for OM diagnosis, increased the sensitivity to 98% (95% CI 95-100), reducing the specificity to 66% (95% CI 53-78), whereas using the positivity of both tests, we obtained a sensitivity of 82% (95% CI 75-90) and a specificity of 92% (95% CI 85-99). The negativity of both tests had a 94% (95% CI 87-100) negative predictive value. Comparison of the areas under the curve showed no differences in the diagnostic accuracy of IPT, SF-EMG, and their combinations. CONCLUSIONS: IPT and SF-EMG have similar diagnostic accuracy in patients with OM presenting with ptosis. The negativity of both tests strongly suggests another diagnosis. CLASSIFICATION OF EVIDENCE: This study provides Class I evidence that both the IPT and SF-EMG accurately identify patients with OM

Muscle sympathetic response to arousal predicts neurovascular reactivity during mental stress.

Mental stress often begins with a sudden sensory (or internal) stimulus causing a brief arousal reaction, and is followed by a more long lasting stress phase. Both arousal and stress regularly induce blood pressure (BP) increases whereas effects on muscle sympathetic nerve activity (MSNA) are variable. Here we have compared responses of MSNA and BP during arousal induced by an electrical skin stimulus andmental stress evoked by a 3min paced auditory serial arithmetic test (PASAT) in 30 healthy males aged 33\ub110 years. In addition, recordings were made of ECG, respiratory movements, electrodermal activity and perceived stress. We also monitored corresponding effects of a cold test (CT: 2 min immersion of a hand in ice water). The arousal stimulus evoked significant inhibition of one or two MSNA bursts in 16 subjects, who were classified as responders; the remaining 14 subjects were non-responders. During mental stress responders showed a significant decrease of MSNA and a lesser BP increase compared to non-responders. In non-responders MSNA was unchanged or increased. Perceived stress was higher in non-responders (P =0.056), but other measures were similar in the two groups. In non-responders mental stress and the cold test induced increases of BP that lasted throughout the subsequent rest period. During the cold test MSNA and BP increased equally in responders and non-responders. In the whole group of subjects, there was a significant correlation (r =0.80, P0.6). Additionally arousal-induced MSNA change was positively correlated with blood pressure changes during MS (systolic BP: r =0.48; P<0.01; diastolic BP: r =0.42; P<0.05) but not with blood pressure changes during CT.We conclude that in males the MSNA response to arousal predicts the MSNA and BP responses to mental stress

Somatic and autonomic small fiber neuropathy induced by bortezomib therapy: an immunofluorescence study.

Bortezomib is a new chemotherapeutic agent approved for the treatment of relapsed/refractory and newly diagnosed multiple myeloma. One of the major side effects of bortezomib is a peripheral length-dependent sensory axonal neuropathy and, less frequently, a small fiber neuropathy. Autonomic symptoms like postural dizziness, syncope, diarrhoea, ileus, impotence and urinary disturbances have been reported, nevertheless, autonomic neuropathy has never been characterized. We describe by means of immunofluorescence, the involvement of autonomic skin nerve fibers in three patients with small fiber neuropathy induced by bortezomib treatmen

Microneurographic evaluation of sympathetic activity in small fiber neuropathy.

Objective: Small fiber neuropathy (SFN) may involve somatic and autonomic fibers. Assessment of somatic epidermal nerve fiber density (ENFs) is considered the gold standard test in the diagnosis of SFN. By contrast, autonomic involvement in SFN is more difficult to ascertain. Here we investigate peripheral sympathetic outflow by microneurography in patients with selective small nerve fiber involvement of different origin with and without autonomic symptoms to ascertain the ability of microneurography and the corresponding skin organ effector responses (sympathetic skin activity-SSR and skin vasomotor reflex-SVR) to disclose autonomic involvement. Methods: We studied 59 patients with SFN because of reduced leg ENFs and normal conduction studies. Thirty patients reported only burning paresthesia (somatic SFN) whereas 29 patients complained of additional autonomic dysfunctions (autonomic SFN). They underwent microneurography from peroneal nerve with the recording of muscle sympathetic nerve activity (MSNA), skin sympathetic nerve activity (SSNA) and the corresponding SSR and SVR in the same innervation field. Thirty age and sex-matched healthy subjects served as controls. Results: Patients with autonomic SFN mainly complained of loss of sweating. They showed a significant absence of indirect (SSR and SVR) and direct (MSNA and SSNA) sympathetic tests compared to somatic SFN patients and controls. SSNA, SSR and SVR were more often absent than MSNA. In addition, SSR and SVR were absent in all patients with no recordable SSNA but no significant relationship was found with MSNA recording. Conclusions: SSR and SVR, simple indirect tests of sympathetic activity, could help to disclose autonomic involvement in SFN with a good sensitivity mainly in patients with sweating dysfunctions although they expressed autonomic failure in only one sympathetic branch. Significance: Microneurographic evaluation of sympathetic activity, technically more difficult than indirect tests, was a useful functional tool contributing to the diagnosis and extension of autonomic involvement in SFN. Our data showed that the skin sympathetic branch is more often involved than the muscle sympathetic branch in SFN