Raffaele Dubbioso

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.

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.

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.

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.

Atypical clinical and radiological presentation of cryptococcal choroid plexitis in an immunocompetent woman

Central nervous system cryptococcal infections usually manifests as meningitis, meningoencephalitis, encephalitis or ventriculitis. Cryptococcal choroid plexus inflammation is a particularly rare entity most often presenting with signs and symptoms of intracranial hypertension, hydrocephalus or meningitis due to a delayed diagnosis. Herein we reported the case of a 63-year-old immunocompetent woman with a history of temporal lobe epilepsy and behavioral disorders. Magnetic resonance imaging (MRI) and fluorodeoxyglucose positron emission tomographic (FDG-PET) images revealed atypical cryptococcal choroid plexitis with surrounding bitemporal edema without features of meningitis, intraparenchymal cryptococcoma or hydrocephalus. The patient underwent serial MRI and FDG-PET images performed before and after antifungal therapy that caused a marked clinical improvement. Our case also suggests a potential role of FDG-PET in the monitoring antifungal therapeutic efficacy.

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

Anti-GAD antibody ocular flutter: expanding the spectrum of autoimmune ocular motor disorders

Antibodies directed against glutamic acid decarboxylase (GAD) have been described in patients with progressive cerebellar ataxia [1] and in a few patients affected by primarily oculomotor disorders [2]. The abnormal eye movements described with anti-GAD antibodies, so far, range from nystagmus (up/down-beat, periodic alternating nystagmus) [2, 3] to opsoclonus [4], but ocular flutter has never been reported. A 69-year-old woman was admitted to our hospital for a 10-month progressive oscillopsia, blurred vision and gait imbalance with significant impairment of daily activities (such as reading a book, watching television and leaving home alone). Neurological examination showed ocular flutter, characterized by intermittent bursts of horizontal conjugate saccades without an intersaccadic interval. The eye oscillations were independent of eye position and occurred during fixation (voluntary and guided changes in gaze position), regardless of gaze direction, with eyes open or closed. The patient had full range of eye motion and did not report diplopia. Unsteadiness with severe retropropulsion was also evident. The remaining neurologic examination was normal. Analysis of ocular movements using video-oculography revealed bursts of rapid horizontal, symmetric movements without intersaccadic interval (Fig. 1a). Results of electrophysiological examinations, such as somatosensory and visual evoked potentials, nerve conduction study and electroencephalography, were normal. Routine blood cell counts and biochemistry were normal. Serological tests, cultures, and polymerase chain reactions performed on blood and cerebrospinal fluid (CSF) samples were negative for viral, bacterial, and fungal infections. Brain magnetic resonance imaging showed no abnormality. Results of screening examinations for neoplasms, including abdominal ultrasonography, computed tomography of the abdomen and chest, as well as whole-body positron emission tomography, were all unremarkable. CSF examination revealed normal protein concentration and no cells, isoelectric focusing showed two oligoclonal bands and the immunoglobulin G index was within the normal range. The patient tested negative for anti-gliadin, paraneoplastic antibodies (anti-Ri, anti-Hu, anti-Yo, antiMa2, anti-CV2 and anti-amphiphysin), anti-LGI1, antiCaspr2, antiganglioside Q1b and anti-NMDA receptor in the serum and CSF. Antibodies against GAD65 were measured by radioimmunoassay. GAD65 antibody titre was increased in serum (2,378 IU/mL, normal value \1 IU/mL) and in CSF (55.7 IU/mL, normal value \1 IU/mL), with an intrathecal synthesis index of 10.64 (normal range 0.7–1.3). An intravenous immunoglobulin (IVIg) treatment (400 mg/kg/day for 5 days) in six cycles once a month was started. The symptoms gradually resolved and continued to improve after the last administration of IVIg and at the same time serum GAD65 antibody titre decreased significantly (Fig. 1c). To avoid clinical relapses, azathioprine 200 mg orally daily was added to the last cycle of IVIg (Fig. 1c). R. Dubbioso F. Manganelli R. Iodice M. Esposito L. Santoro (&) Department of Neuroscience, Reproductive Sciences and Odontostomatology, University of Naples ‘‘Federico II’’, Via Sergio Pansini, 5, 80131 Naples, Italy e-mail: lusantor@unina.it

Subclinical neurological involvement does not develop if Wilson's disease is treated early

BACKGROUND & AIMS Wilsons disease (WD) is a genetic disorder of copper metabolism causing dysfunctions of various organs, mostly the liver and brain. If untreated, WD is fatal, but early treatment results in a good prognosis, although the long-term neurological outcome has not yet been clarified. To address this issue, we evaluated the neurological status of early-treated WD patients without overt nervous system impairment using neurophysiological, neuropsychological and neuroimaging procedures at least 10 years after treatment onset. METHODS Thirty-eight WD patients (18 females, aged 24.47 ± 7.50 years), who received an early diagnosis (in presymptomatic or mild/moderate liver disease stages without neurological involvement) and prompt treatment, were clinically evaluated with the Global Assessment Scale. Presentation was hepatic in 36 subjects (95%), while 2 patients (5%) were presymptomatic. A neurophysiological study was performed to explore the central motor conduction time of the upper and lower limbs, and motor cortex excitability using single pulses and paired-pulse transcranial magnetic stimulation. Neuroimages were obtained with brain magnetic resonance scans. Cognitive abilities, and psychiatric and behavioral disturbances were evaluated with neuropsychological tests. RESULTS Patients were undergoing treatment with penicillamine (7 patients) or zinc salts (31 patients) with good adherence. They did not present any neurological signs at clinical evaluation or at specific scale of impairment, the mean Global Assessment Scale score was 0.3 ± 0.7. Magnetic resonance imaging, transcranial magnetic stimulation studies and neuropsychological/neuropsychiatric assessment ruled out subclinical involvement. CONCLUSIONS This study suggests that early diagnosis and treatment of WD may prevent the onset of neurologic damage, even at subclinical level.