Panagiotis Kokotis

Large and small fiber neuropathy in chronic alcohol-dependent subjects.

Abstract  The aim of the present study was to evaluate the occurrence of large and small fiber neuropathy among alcohol‐dependent subjects and to correlate neuropathy with the pattern of alcohol abuse, age of the subjects, nutritional status, and biochemical parameters. The study sample comprised 98 consecutive alcohol‐dependent subjects without signs of malnutrition treated for detoxification voluntarily in the specialized unit of the Athens University Psychiatric Clinic in an inpatient basis. Polyneuropathy (PN) was graded using the neuropathy symptoms score and neurologic disability score, conduction velocity studies, and quantitative sensory tests. Seventy‐seven men and 21 women aged 27–70 years took part in the study. PN was diagnosed in 57 subjects (58.2%). PN of both large and small fibers was found in 25 patients (25.5%); exclusively small fiber neuropathy was observed in 12 (12.2%) and exclusively large fiber neuropathy in 20 patients (20.4%). Neuropathy was significantly correlated with the age of the subjects, duration of alcohol abuse, liver dysfunction, macrocytosis, and blood sugar levels upon admission. PN was significantly more frequent in males than in females. The two groups of exclusively large and exclusively small fiber neuropathy did not differ significantly in any clinical and laboratory parameter. Subclinical neuropathy (stage 1) was observed in 11.2%, which also did not differ significantly in any clinical and laboratory parameter from the stage 2 PN group subjects. Our findings indicate the direct toxic effect of alcohol on peripheral nerve fibers as the main etiologic factor of alcoholic PN. Long‐standing hyperglycemia may be another contributing factor. Impaired vitamin B12 utilization may be also involved.

Impaired interhemispheric inhibition in amyotrophic lateral sclerosis

The pathogenesis of sporadic amyotrophic lateral sclerosis (ALS) remains unknown. Neurophysiological studies provide evidence of hyperexcitability of the motor cortex or of impairment of inhibitory intrahemispheric modulation of the corticomotoneuron in ALS. In this paper, we used TMS to elicit transcallosal inhibition of the motor cortex in ALS patients in order to investigate whether interhemispheric inhibitory mechanisms subserved by callosal fibres are also disturbed in ALS. Twenty‐five patients with ALS and 18 controls were recruited for the study. Resting Motor Threshold (RMT), Silent Period (SP) and interhemispheric inhibition (IHI) were recorded. No significant difference was detected regarding RMT or the duration of SP between patients and controls. IHI was detected in all controls. IHI was totally absent in eight patients, in another eight patients IHI did not reach a significant level and in the remaining nine patients was normal. The degree of IHI was significantly lower in ALS patients than in controls (p = 0.001). In conclusion, altered IHI in ALS patients is in line with the general pattern of reduced corticomotoneuron inhibition, being thus, one of the factors which may lead to chronic overexcitation of pyramidal cells.

Polyneuropathy induced by HIV disease and antiretroviral therapy

OBJECTIVE To investigate the underlying mechanisms of polyneuropathy induced by HIV infection or antiretroviral drugs. METHODS We tested 100 HIV patients (59 with AIDS). Ninety-three patients received antiretroviral drugs. Forty-four were treated with neurotoxic compounds (ddI, ddC, d4T). Nerve conduction velocities and the sympathetic skin response (SSR) in palms and soles were measured in all patients. In skin biopsies (ankle and thigh), the intraepidermal nerve fiber density (IENFD) and the number of epidermal fibers without contact to the basal membrane (fragments) were quantified using PGP9.5 staining. RESULTS Severity of the disease (CD4 +count) correlated to conduction velocities of peroneal (p < 0.01, Spearmans rank correlation), sural (p < 0.01) and median nerves (p < 0.05/p < 0.001, sensory/motor). In contrast, the duration of neurotoxic treatment did not impair conduction velocities (p > 0.3) but correlated to reduced IENFD in the ankle (r = -0.24, p < 0.05). Despite their reduced IENFD, patients with long neurotoxic treatment had a high number of fragments irrespective of their CD4 +count. CONCLUSIONS Neurotoxic treatment appears to primarily impair thin fiber conduction, whereas HIV neuropathy is linked to large fiber impairment and reduction of fragments of nerve fibers. SIGNIFICANCE These findings emphasize the differential pattern of polyneuropathy in HIV patients caused by the infection or induced by antiretroviral treatment.

Double seronegative myasthenia gravis with low density lipoprotein-4 (LRP4) antibodies presenting with isolated ocular symptoms.

The detection of low density lipoprotein-4 (LRP4) antibodies in double seronegative (dSN) myasthenia gravis (MG) patients has provided new insights in the diagnosis and treatment of MG. However, there are limited data regarding the clinical presentation and treatment response in dSN MG patients with LRP4-antibodies. We present a case series of three Caucasian dSN MG patients with positive LRP4-antibodies sharing a common ethnic background that presented with isolated ocular symptoms (MGFA I). The demographic and clinical characteristics, the diagnostic work-up as well as the treatment response during a follow-up period of 12-24 months are described in detail. All patients were treated successfully with acetylcholinesterase inhibitors (AcheI) and prednisone with two exhibiting full remission of their symptoms, while the remaining exhibited mild residual diplopia. Notably, we documented no signs of generalized disease progression, while no patient required immunosuppressive treatment. In conclusion, the distinct clinical phenotype of our patients highlights the clinical relevance of screening for LRP4-antibodies in patients presenting with isolated ocular MG independent of age and gender, since it may lead to the timely diagnosis of MG and prompt initiation of effective therapy with ACheI and corticosteroids.

Oxaliplatin-Induced Neuropathy: A Long-Term Clinical and Neurophysiologic Follow-Up Study

BACKGROUND Oxaliplatin is an effective drug used mainly for advanced colorectal cancer. Neurotoxicity is the major side effect of oxaliplatin. The present clinical and neurophysiologic study was conducted to evaluate patients receiving oxaliplatin therapy. PATIENTS AND METHODS Thirty-one consecutive patients with colorectal cancer who received oxaliplatin therapy were followed up for more than 3 years. The patients underwent clinical and neurophysiologic tests for large and small fiber function at every visit. RESULTS Most of the patients received oxaliplatin-based chemotherapy at the initial dose of 130 mg/m(2) for 6 to 8 cycles, normally every 3 weeks. Acute neurotoxicity with cold and mechanical hyperalgesia was reported by the vast majority of patients after each cycle of therapy and was confirmed by the quantitative sensory, filament, and axon reflex test. Chronic sensory cumulative neuropathy developed in most of the patients after the middle of therapy with numbness and was assessed using clinical scales, nerve conduction studies, and the vibration threshold. Our results support the persistence of the sensory nerve deficits for years after cessation of oxaliplatin therapy. CONCLUSION Our study has confirmed the results of a few previous long-term studies concerning the persistence of chronic large sensory fiber neuropathy and the influence of the cumulative dose of oxaliplatin on the development and severity of the chronic neuropathy. Our findings have improved the knowledge about the acute oxaliplatin-induced neurotoxicity using the C-fiber axon reflex response.

Repetitive Nerve Stimulation of Facial and Hypothenar Muscles: Relative Sensitivity in Different Myasthenia Gravis Subgroups

Aim: To assess the utility of repetitive nerve stimulation (RNS) in facial and hypothenar muscles in the clinical groups of myasthenia gravis (MG). Patients and Methods: We performed RNS study in the orbicularis oculi (O.O.), nasalis and abductor digiti quinti (ADQ) in 115 consecutive myasthenic patients and classified them according to the classifications of the Myasthenia Gravis Foundation of America. Patients were classified into three groups: group 1, group 2 (IIa, IIIa and IVa) and group 3 (IIb, IIIb and IVb). Results: RNS was abnormal in 95 patients (82.6%): 78.3% in the O.O., 66.1% in the nasalis and 19.1% in the ADQ. Both facial muscles were statistically more sensitive than the ADQ in all groups of patients. RNS in the O.O. was more frequently abnormal than in the nasalis only in group 1. Sensitivity to acetylcholine antibodies in myasthenic patients was 84%. Acetylcholine receptor (AChR) and muscle-specific tyrosine kinase antibodies were present in 96.7% of the patients with abnormal RNS in both facial muscles. Single-fiber electromyogram (SFEMG) was abnormal in 91.3% of the tested patients. One of the three tests used for the diagnosis of MG (AChR antibodies, SFEMG, RNS) was abnormal in 99.1% of the patients. Discussion: O.O. is the most sensitive muscle in all groups of MG followed by nasalis, while the ADQ is the muscle with the lowest sensitivity. Facial muscles, especially the O.O., should be the first to be tested in MG. The negativity of all tests (RNS, AChR antibodies, SFEMG) should question the diagnosis of MG, even in the presence of symptoms consistent with MG.

Urinary frequency in a case of Neuro-Behcet disease involving the brainstem—Clinical, electrophysiological and urodynamic features

Micturitional disturbances are reported in 5-20% of patients with Behcet disease (BD) affecting the central nervous system. However, corresponding data regarding urodynamic and electrophysiological findings are limited. A patient with known BD presented with dysarthria, diplopia and urinary frequency (36 times/day). MRI revealed an extensive lesion involving the lateral and tegmental pons, reaching the pontomedullary junction. Auditory evoked potentials indicated a left-side lesion between superior olivary nucleus and superior colliculus. Blink reflex examination indicated a location caudal to the left trigeminal root. Pudendal nerve somatosensory evoked potentials and transcranial magnetic stimulation of the perineal muscles were slightly affected. Bulbocavernosus reflex latencies were normal. EMG of the bulbocavernosus muscles showed a normal maximal voluntary contraction activity. Urodynamic studies revealed normal urine volume, maximum flow rate and residual volume. After intravenous administration of methylprednisolone diplopia and dysarthria resolved within 3 weeks. Urinary frequency remained almost unchanged for the first 8 weeks, but clearly improved during the following months. We assume that the present case of urinary frequency is the result of vasculitic lesion affecting the pontine micturition inhibitory area on the ground of Neuro-Behcet disease.

Differential sensitivity of thick and thin fibers to HIV and therapy-induced neuropathy

The study assessed HIV-related and anti-retroviral therapy-induced neuropathy in myelinated and unmyelinated nerve fibers. One hundred consecutive HIV patients were examined clinically and standard nerve conduction velocities were measured. In addition, electrically induced sympathetic skin response (SSR) was assessed in the palms and soles. The difference in delay of SSR in palms and soles (DeltaSSR) was calculated as an indirect measure of C-fiber conduction velocity. Thick fiber conduction velocities significantly decreased with age and increasing stage of the disease, whereas no effect of stage was found for DeltaSSR (p=0.6). In contrast, medication of at least one of the most known neurotoxic drugs zalcitabine, stavudine, or didanosine did not result in significantly lower conduction velocities in thick fibers (51.29+/-3.4 m/s vs. 50.86+/-3.5 m/s), but was related to an increased DeltaSSR. DeltaSSR allows an indirect measurement of C-fiber conduction velocity. In HIV this measure of unmyelinated sympathetic fibers was most sensitive to anti-viral treatment whereas conduction velocity of myelinated somatic fibers was more sensitive to disease-related neuropathy. The results suggest that HIV neuropathy preferably affects myelinated and anti-retroviral therapy unmyelinated fibers.

Nomogram for determining lower limit of the sural response

OBJECTIVE Age and height influence on sural sensory nerve action potential (SNAP) have been studied separately. Our aim was to develop an equation for predicting the lower normal limits as a function of both these factors. METHODS One hundred fifty-eight healthy volunteers, 63 male, with mean age 45.8 and mean height 167.3 without symptoms or signs of peripheral neuropathy participated in the study. The sural SNAP was recorded at the level of the ankle joint, just posterior to the lateral malleolus, using surface electrodes. Antidromic supramaximal stimulation was performed 13 cm proximally at the posterior midcalf. RESULTS The mean sural SNAP amplitude was 19.9+/-6.89 microV. Pearson linear correlation showed a negative correlation of the SNAP amplitude with age (R=-0.22, p=0.005) and height (R=-0.19, p=0.03). The multiple linear regression model was applied for both parameters of age and height with SNAP amplitude as the dependent parameter, producing the following equation: SNAP amplitude=62.45-0.1447 x Age-0.2147 x Height. CONCLUSIONS Using our normal data, the computed lower limits of the 95% prediction interval for the sural SNAP amplitude of an individual subject, depending on his age and height, were calculated. SIGNIFICANCE The individualized normal values provided by our equation are essential for the correct interpretation of sural nerve studies.

Concurrent bilateral projection and activation of motor cortices in a patient with congenital mirror movements: a TMS study.

OBJECTIVES Mirror movements (MMs) are unintended and unnecessary movements accompanying voluntary activity in homologous muscles on the opposite side of the body, particularly in distal arm muscles. Congenital MMs may be sporadic or familial. Several mechanisms have been proposed to explain persistent congenital MMs. Hypothesis 1 assumes the existence of an ipsilateral corticospinal pathway, and Hypothesis 2 the activation of both motor cortices. We report a new case of congenital mirror movements in a healthy woman. METHODS Electromyographic recordings and focal transcranial magnetic stimulation (TMS) were used for neurophysiological evaluation. RESULTS Voluntary contraction of either abductor pollicis brevis (APB) elicited mirror activation of the other APB. Focal TMS of either M1 elicited motor evoked potential (MEP) of normal latency and amplitude in both resting APB. TMS of the left cortex upon maximal contraction of the right APB and mirror contraction of the left APB produced interhemispheric inhibition (IHI) in the former and silent period (SP) in the later. CONCLUSIONS The electrophysiological evaluation using transcranial magnetic stimulation provides evidence of the concurrent action of both mechanisms in this patient. SIGNIFICANCE The combination of more than one hypothesis could be more appropriate for understanding the underlying mechanism in some MM cases.