Chiara Pisciotta

Functional involvement of central cholinergic circuits and visual hallucinations in Parkinson's disease

Visual hallucinations (VHs) represent a frequent and disturbing complication of Parkinsons disease. Evidence suggests that VH can be related to central cholinergic dysfunction. Short-latency afferent inhibition (SAI) technique gives the opportunity to test an inhibitory cholinergic circuit in the human cerebral motor cortex. This inhibition of motor-evoked potentials can be observed when transcranial magnetic stimulation is delivered with a delay ranging from 2 to 8 ms, after a peripheral nerve afferent input has reached the somatosensory cortex. We applied SAI technique in 10 non-demented patients with Parkinsons disease with VHs, in 12 non-demented patients with Parkinsons disease without VHs (NVH-pts) and in 11 age-matched normal controls. All patients with Parkinsons disease underwent a battery of neuropsychological tests to assess frontal and visuospatial functions, memory and attention. SAI was significantly reduced in patients with VHs compared with controls and patients without VHs. Neuropsychological examination showed a mild cognitive impairment in 16 out of 22 patients with Parkinsons disease. In addition, we found that in our patients with VHs, performance of some tasks evaluating visuospatial functions and attentional/frontal lobe functions was significantly more impaired than in patients without VHs. SAI abnormalities, presence of VH and neuropsychological results strongly support the hypothesis of cholinergic dysfunction in some patients with Parkinsons disease, who will probably develop a dementia. A follow-up study of our patients is required to verify whether SAI abnormalities can predict a future severe cognitive decline. Moreover, SAI can also be very useful to follow-up the efficacy of anti-cholinesterase therapies.

Small-fiber involvement in spinobulbar muscular atrophy (Kennedy's disease)

We assessed the involvement of cutaneous innervation in two subjects with a molecularly confirmed diagnosis of spinobulbar muscular atrophy (SBMA) using antidromic nerve conduction studies, quantitative sensory testing, and sweat tests, as well as immunohistochemical techniques and confocal microscopy of glabrous and hairy skin biopsy. Both patients showed a marked reduction in amplitude of sensory action potentials and moderate or severe abnormalities of tactile thresholds and mechanical pain perception. A severe reduction of sweat drops on the Silastic imprint test and a widespread loss of small myelinated and unmyelinated fibers in hairy skin were also observed. Fiber loss involved either somatic or autonomic fibers and did not show any distal–proximal gradient. These results, together with loss of Meissner corpuscles and their large myelinated afferent fibers in glabrous skin, confirmed the extensive involvement of sensory neurons of large and small size and revealed an autonomic skin denervation in SBMA. Muscle Nerve, 2007

Electrophysiological characterisation in hereditary spastic paraplegia type 5

OBJECTIVE To assess in SPG5 hereditary spastic paraparesis (HSP) the involvement of the central (CNS) and the peripheral (PNS) nervous system by a multimodal electrophysiological approach. METHODS Four patients belonging to three HSP families, with a molecular diagnosis of SPG5, underwent electrophysiological evaluation including electromyography (EMG) and nerve conduction study (NCS), motor-evoked potentials (MEPs) by transcranial magnetic stimulation (TMS) and somatosensory evoked potentials (SEPs) at upper and lower limbs, visual (VEPs) and brainstem auditory evoked potentials (BAEPs). In one patient, electrophysiological evaluation was performed twice at the age of 12 and 31 years. RESULTS EMG and NCS were normal. MEPs and SEPs were abnormal in all patients along the central pathway for upper and/or lower limbs. VEPs revealed a damage of visual pathway and BAEPs showed the involvement of auditory pathway within the brainstem. In the patient who underwent electrophysiological follow-up, MEP and SEP findings were unmodified, whereas VEPs showed no reproducible responses. CONCLUSIONS We report an extensive electrophysiological evaluation of SPG5 and we confirm that the SPG5 phenotype may be broader than pure presentation. SIGNIFICANCE Electrophysiological evaluation, showing diffuse CNS involvement with PNS sparing, could be very useful to address the molecular diagnosis and to follow-up a hypothetical treatment.

Influence of comorbidities on the phenotype of patients affected by Charcot–Marie–Tooth neuropathy type 1A

Charcot-Marie-Tooth type 1A (CMT1A) is the most common inherited neuropathy. The phenotype of patients affected by CMT1A is highly variable and may be influenced by several conditions. We evaluated how comorbidities such as diabetes, hypothyroidism, exposure to toxins and obesity can modify or exacerbate the clinical and neurophysiological phenotype of CMT1A patients. Disability was measured using the classic CMT neuropathy score. Compared to controls, all groups of CMT1A patients with comorbidities had higher CMT neuropathy score. In particular, patients with CMT1A and diabetes mellitus show motor subscores which are significantly higher than in control CMT1A. Amplitudes of ulnar CMAP are lower in patients with CMT1A and diabetes mellitus, but not at a significant level. As expected, motor nerve conduction velocity is not influenced by any of the comorbidities. The presence of concomitant diseases shows a tendency to worsen the clinical and neurophysiological CMT1A phenotype, especially in patients with CMT1A and diabetes mellitus, where higher values in the CMT neuropathy score and clinical motor subscore have been observed.

A new Italian FHM2 family: clinical aspects and functional analysis of the disease-associated mutation.

Objective: To describe a new FHM kindred, and to analyse the functional consequences of the disease-associated ATP1A2 p.G301R mutation in human cellular models grown at 37°C. Patients and methods: Seven patients were clinically evaluated and gave informed consent for molecular analysis. Extra-pyramidal rigidity of the limbs was present in four subjects and in three of them tongue apraxia was also observed. ATP1A2 and CACNA1A were analysed by direct sequencing. Functional consequences of the mutation were investigated by cell viability assays, Western blots, and immunocytochemistry. Three-dimensional models of the human Na+/K+-ATPase α2 subunit were generated by homology modelling using SWISS-MODEL. Findings: Analysis of ATP1A2 showed a heterozygous mutation, c.901G>A predicting the replacement of arginine for glycine at residue 301 (p.G301R). Functional analysis suggested that the mutation completely abolished Na+/K+-ATPase function. Conclusions: The phenotypic spectrum of our FHM2 family includes some peculiar features. Functional data confirm that Na+/K+-ATPase haploinsufficiency caused by the ATP1A2 p.G301R mutation is responsible for FHM in the described family.

Somatosensory Temporal Discrimination Threshold Is Increased in Patients with Cerebellar Atrophy

Processing of time in the millisecond range seems to depend on cerebellar function and it can be assessed by using the somatosensory temporal discrimination threshold testing. No studies have yet investigated this temporal discrimination task in patients with cerebellar atrophy. Eleven patients with degenerative cerebellar ataxia and 11 controls underwent somatosensory temporal discrimination threshold evaluation. The degree of cerebellar dysfunction was measured by the International Cooperative Ataxia Rating Scale. Somatosensory temporal discrimination threshold was higher in patients compared to controls for each stimulated site (hand, neck, and eye). Age, disease duration, and International Cooperative Ataxia Rating Scale scores were not correlated to somatosensory temporal discrimination threshold. Somatosensory temporal discrimination threshold is abnormal in patients with cerebellar atrophy. These findings suggest that the cerebellum plays a role in modulating the somatosensory temporal discrimination threshold and confirm the role of cerebellum in the processing of time in the millisecond range.

Small nerve fiber involvement in CMT1A.

Objective: To assess the involvement of small nerve fibers in Charcot-Marie-Tooth type 1A (CMT1A). Methods: We used indirect immunofluorescence and confocal microscopy on punch biopsies from glabrous (fingertip) and hairy (thigh and leg) skin of 20 unrelated patients with CMT1A to quantify somatic and autonomic nerve fibers. In particular, we quantified epidermal nerve fibers (ENF), Meissner corpuscles (MC), intrapapillary myelinated endings (IME), and sudomotor nerves. We correlated morphologic data with findings from quantitative sensory testing, sudomotor output, sympathetic skin response, and cardiovascular reflexes. A control population of healthy age- and sex-matched controls was included with a matching ratio of 1:2. Results: We found a length-dependent loss of ENFs that worsened with aging. We also observed a loss of MCs, IMEs, and sudomotor nerves. The loss of ENF at distal leg correlated with the increase in heat-pain thresholds (p < 0.05) and with tactile thresholds (p < 0.05). Sudomotor nerve fiber loss correlated with ENF density (p < 0.05) and sweating output (p < 0.001). Conclusions: We demonstrated through morphologic, physical, and psychophysical testing that small somatic and autonomic fibers are abnormal and cause symptoms in patients with CMT1A. Awareness of such symptoms by the clinician could lead to better treatment.

Nerve conduction velocity in CMT1A: what else can we tell?

Charcot‐Marie‐Tooth disease (CMT) type 1A is characterized by uniformly reduced nerve conduction velocity (NCV) that is fully penetrant since the first years of life, remains fairly stable through the life and does not correlate with disability whereas compound muscular action potential (CMAP) amplitude does. The aim of the present study was to analyze the large amount of electrophysiological data collected in the ascorbic acid trial in Italy and the UK (CMT‐TRIAAL/CMT‐TRAUK) and to use these data to gain insights into the pathophysiology of NCV in CMT1A.

Autoimmune Autonomic Ganglionopathy A Possible Postganglionic Neuropathy

OBJECTIVE To evaluate postganglionic autonomic and somatic nerve fiber involvement in a patient with chronic autoimmune autonomic ganglionopathy. DESIGN Case report. SETTING Department of Neurological Sciences, University Federico II of Naples. PATIENT A patient with a 16-year history of severe autonomic failure and a high nicotinic acetylcholine receptor antibody titer underwent an extensive laboratory evaluation. MAIN OUTCOME MEASURES Evaluation of sympathetic and parasympathetic functions and sural nerve and skin biopsies. RESULTS Clinical and laboratory evaluations showed the involvement of cardiovascular, pupillary, sudomotor, gastrointestinal, and bladder functions. Sudomotor function study and skin biopsy findings revealed postganglionic autonomic damage. Moreover, sural nerve and skin biopsy specimens provided clear evidence of somatic nerve fiber involvement. CONCLUSIONS We demonstrated postganglionic autonomic damage that could be related to a prolonged and severe impaired synaptic transmission and we report, for the first time to our knowledge, a somatic nerve fiber involvement in autoimmune autonomic ganglionopathy.

Case of acute motor conduction block neuropathy (AMCBN).

We describe a 21 year‐old man with an acute development of weakness whose clinical and serial electrophysiological findings were atypical for Guillain–Barré syndrome. Electrophysiological data suggested a diagnosis of “acute motor conduction block neuropathy” (AMCBN). The 6 months of disease duration and the electrophysiological follow‐up, which never showed axonal degeneration until complete clinical recovery, raise the issue of the relationship between AMCBN and acute motor axonal neuropathy (AMAN). Muscle Nerve 39: 224–226, 2009