Rosa Iodice

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.

Neuropathy and levodopa in Parkinson's disease: Evidence from a multicenter study

The objectives of this study were to evaluate the risk of neuropathy in patients with Parkinsons disease (PD) and to evaluate the role of levodopa exposure as a potential risk factor. A multicenter study of 330 patients with PD and 137 healthy controls with a comparable age distribution was performed. With respect to levodopa exposure, 144 patients had long exposure (≥3 years) to levodopa (LELD), 103 patients had short exposure (<3 years) to levodopa (SELD), and 83 patients had no exposure to levodopa (NOLD). Nerve function was evaluated using the reduced total neuropathy score. Right sural sensory antidromic and peroneal motor nerve conduction studies were performed by neurophysiologists who were blinded to the existence of neuropathy clinical features or PD treatment. Overall, 19.40% of patients in the LELD group, 6.80% in the SELD group, 4.82% in the NOLD group, and 8.76% in the control group were diagnosed with neuropathy (axonal, predominantly sensory). Multivariate logistic analysis indicated that the risk of neuropathy was not influenced by disease duration, severity, or sex. The risk of neuropathy increased by approximately 8% for each year of age (P < 0.001; odds ratio [OR], 1.08; 95% confidence interval [CI], 1.037‐1.128). The risk of neuropathy was 2.38 higher in the LELD group than in the control group (P = 0.022; OR, 2.38; 95% CI, 1.130‐5.014). In a comparison between patients with and without neuropathy (Students t test), the levodopa dose was higher (P < 0.0001), serum vitamin B12 levels were lower (P = 0.0102), and homocysteine levels were higher (P < 0.001) in the patients with neuropathy. Our results demonstrate that the duration of exposure to levodopa, along with age, is the main risk factor for the development of neuropathy. Screening for homocysteine and vitamin B12 levels and clinical‐neurophysiological monitoring for neuropathy may be advisable in patients with PD who are receiving treatment with levodopa.

Postganglionic sudomotor denervation in patients with multiple system atrophy

Objective: To evaluate postganglionic autonomic involvement in multiple system atrophy (MSA). Methods: We quantified sudomotor innervation in skin biopsy of 29 patients with MSA (19 male and 10 female; age 60.0 ± 7.7 years) and 29 age- and sex-matched healthy subjects. Samples were obtained from thigh and leg and, in 20 out of the 29 cases, also from fingertip. Dysautonomic complaints were evaluated by SCOPA-AUT, a self-administered questionnaire. Sudomotor function was evaluated in a subgroup of patients by the silastic imprint test. Skin samples were processed by indirect immunofluorescence using pan-neuronal and selective cholinergic markers. Total length of sudomotor nerves was measured on digital confocal images using a semiautomated morphometric approach. Results: Measurements of sudomotor nerve density (total length of nerve per volume of glandular tissue) favorably correlated to values obtained using a stereologic unbiased method. Sudomotor nerve density was lower in patients compared to controls in all the examined sites (0.9 ± 0.2 vs 1.9 ± 0.4 nm/μm3, p < 0.001, in fingertip; 0.7 ± 0.2 vs 1.9 ± 0.5 nm/µm3, p < 0.001, in thigh; 0.6 ± 0.2 vs 1.8 ± 0.4 nm/µm3, p < 0.001, in leg). Conclusions: Our data support the hypothesis that postganglionic impairment occurs in MSA and may contribute with the coexisting degeneration of central structures to the development of dysautonomic disorders in this condition.

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.

Central cholinergic dysfunction in the adult form of Niemann Pick disease type C: a further link with Alzheimer’s disease?

Adult patients with Niemann-Pick disease type C (NPC) usually develop cognitive impairment progressing to dementia, whose pathophysiology remains still unclear. Noteworthy parallels exist in cognitive impairment and cellular pathology of NPC and Alzheimer’s disease (AD). In particular, alterations of cholinergic system, which represent one of the pathological hallmarks and contribute to cognitive deterioration in AD, have recently been demonstrated in a human brain autopsy and in an experimental model of NPC. This finding raised the issue that central cholinergic circuits dysfunction may contribute to pathophysiology of cognitive impairment in NPC as well, and prompted us to evaluate the cholinergic functional involvement in NPC patients by applying a neurophysiologic technique, named short-latency afferent inhibition (SAI). We describe clinical, biochemical, molecular and neuropsychological features, and SAI findings in three patients affected by NPC. Diagnosis of NPC was assessed by molecular analysis of the NPC1 gene in all patients. In two of them, biochemical analysis of intracellular accumulation of unesterified cholesterol was also performed. The main clinical features were cerebellar ataxia, vertical supranuclear gaze palsy and a variable degree of cognitive impairment ranging from only memory impairment to severe dementia. Electrophysiological evaluation revealed a reduced SAI in all three patients. Our SAI findings provide evidence of cholinergic dysfunction in patients with the adult form of NPC, supporting that cholinergic alterations may play a role in cognitive impairment in NPC, and strengthening the similarities between NPC and AD.

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.

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.

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.

Anodal transcranial direct current stimulation of motor cortex does not ameliorate spasticity in multiple sclerosis

PURPOSE To assess whether anodal transcranial direct current stimulation (tDCS) is effective in modulating lower limb spasticity in MS patients. Previously, anodal tDCS has been shown to improve motor deficits in several neurological diseases and, recently, it has been proposed as effective in decreasing spasticity after stroke. However, the effect of anodal tDCS on spasticity is not examined in MS. METHODS We performed a single-centre randomized, double-blind, sham-controlled study to investigate efficacy of anodal vs sham tDCS in 20 relapsing-remitting MS patients. Ten patients received anodal tDCS stimulation to the primary motor cortex of the more affected side, 20 minutes/day for 5 consecutive days. Ten patients received sham tDCS stimulation. Spasticity was assessed by using the modified Ashworth scale (MAS), the self-scoring MSSS-88 (Multiple Sclerosis Spasticity Scale) and Multiple Sclerosis Walking Scale (MSWS-12) at baseline and at the end of protocol stimulation. RESULTS No side effects were detected during either anodal tDCS or sham. In both groups, there was no significant improvement in MAS, MSSS-88 and MSWS-12 scores. Moreover the comparison between anodal tDCS and sham showed no difference. CONCLUSIONS Five-daily sessions of anodal tDCS to the primary motor cortex does do not improve lower limb spasticity in MS patients.

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.