Diffusion-weighted imaging in patients with progressive multifocal leukoencephalopathy.

Progressive multifocal leukoencephalopathy (PML) is a severe demyelinating disease of the central nervous system due to JC polyoma virus infection of oligodendrocytes. PML develops in patients with impaired T-cell function as occurs in HIV, malignancy or immunosuppressive drugs users. Until now no imaging methods have been reported to correlate with clinical status. Diffusion-weighted imaging (DWI) is a robust MRI tool in investigating white matter architecture and diseases. The aim of our work was to assess diffusion abnormalities in focal white matter lesions in patients with PML and to correlate the lesion load measured with conventional MRI and DWI to clinical variables. We evaluated eight patients with a biopsy or laboratory-supported diagnosis of PML. All patients underwent MRI including conventional sequences (fluid attenuated inversion recovery-FLAIR) and DWI. Mean diffusivity (MD) maps were used to quantify diffusion on white matter lesions. Global lesion load was calculated by manually tracing lesions on FLAIR images, while total, central core and peripheral lesion loads were calculated by manually tracing lesions on DWI images. Lesion load obtained with the conventional or DWI-based methods were correlated with clinical variables such as disease duration, disease severity and survival. White matter focal lesions are characterized by a central core with low signal on DWI images and high MD (1.853 x 10(-3) mm2/s), surrounded by a rim of high signal intensity on DWI and lower MD (1.1 x 10(-3) mm2/s). The MD value of normal-appearing white matter is higher although not statistically significant (0.783 x 10(-3) mm2/s) with respect to control subjects (0.750 x 10(-3) mm2/s). Inter-rater correlations of global lesion load between FLAIR (3.96%) and DWI (3.43%) was excellent (ICC=0.87). Global lesion load on FLAIR and DWI correlates with disease duration and severity (respectively, p=0.037, p=0.0272 with Karnofsky scale and p=0.0338 with EDSS on FLAIR images; p=0.043, p=0.0296 with Karnofsky scale and p=0.0365 with EDSS on DW images). Central core lesion load on DWI correlates with disease duration and severity (respectively p=0.043, p=0.0103 with Karnofsky scale and p=0.0112 with EDSS), while peripheral lesion load does not correlate with any clinical variable. The global lesion load in PML correlates with disease duration and severity. DWI images, which can distinguish within lesions a central core from a peripheral rim, reveal that a larger central core component correlates to a worsened clinical status and longer disease duration. On the other hand the peripheral rim lesion load visualized on DWI images does not correlate with clinical variables and does not achieve obtaining further prognostic information with respect to conventional imaging.

Motor and somatosensory evoked potentials in Autosomal Dominant Hereditary Spastic Paraparesis (ADHSP) linked to chromosome 2p, SPG4.

The aim of our study was to evaluate Motor Evoked Potentials (MEPs) and cortical excitability, using Transcranial Magnetic Stimulation (TMS) as well as short latency Somatosensory Evoked Potentials (SEPs) in Autosomal Dominant Hereditary Spastic Paraparesis (ADHSP) patients. MEPs were recorded from upper and lower limb muscles in 12 patients (7 m and 5f) affected by ADHSP with spastin mutation (SPG4). We measured: (i) motor threshold (MTh); (ii) total motor conduction time (TMCT); (iii) direct and indirect central motor conduction time (d-CMCT and i-CMCT) calculated by subtracting from the cortical latency those obtained on magnetic spinal stimulation (d-PMCT) and via the F-wave method (i-PMCT); (iv) MEP amplitude (MEP/Mmax ratio%) and (v) duration of the cortical silent period (CSP). Latency, amplitude and persistence of the F-wave obtained with electrical nerve stimulation were also considered; H reflex was also tested from lower extremities. SEPs were recorded from spine and scalp sites following median and posterior tibial nerve stimulation; conventional latency and amplitude measurements were performed. In a comparison with the control group, the MTh recording from lower limbs was significantly higher (67.5 +/- 7.7% versus 52.5 +/- 6.9%), MEPs were absent in one case and showed reduced amplitude in the remainders (22.9 +/- 12.6% versus 66.3 +/- 25.9% of M wave); TMCT resulted to be abnormal (36.5 +/- 3.9 ms versus 27.1 +/- 1.4 ms) and d-CMCT as well as i-CMCT were significantly prolonged (23.1 +/- 3.5 ms versus 13.8 +/- 1.3 ms; and 20.1 +/- 3.4 ms versus 10.6 +/- 1.3 ms, respectively). The CSP, which was normal from the hands, was significantly shortened from the legs and correlated with spasticity scoring (Ashworth scale). Cortical SEPs from lower limbs were abnormal in all cases, whereas SEPs by stimulation of median nerves were normal; F-wave parameters from upper limbs showed no abnormalities, whereas an increased persistence was detected from lower limbs; H reflex amplitudes resulted larger compared with controls. Moreover, shortening of the CSP, being correlated with the Ashworth scale, can be considered an electrophysiological marker of spasticity that seems to arise from impairment of the supraspinal or intracortical inhibitory pathways with an additional contribution of increased segmental motor neuron excitability. These data prove the existence of comparable neurophysiological abnormalities in ADHSP with spastin mutation (SPG4) when long ascending and descending pathways are involved.

Brain perfusion effects of cholinesterase inhibitors in Parkinson's disease with dementia.

Several evidences suggest that cholinergic deficits may significantly contribute to dementia in Parkinson's disease (PDD) and acetylcholinesterase inhibitors (ChEIs) have been reported to improve cognitive symptoms in PDD, without worsening parkinsonism. Nineteen PDD patients underwent brain perfusion SPECT with (99m)Tc-ethyl cysteinate dimer after 6 months ChEIs treatment in order to evaluate the functional correlates of clinical improvement. A clear-cut cognitive improvement was reported in PDD patients with a significant improvement of ADAS-cog total score as well as of subscores exploring executive functions (p<0.01). MMSE total score did not significantly change after ChEIs but the subscore of attention significantly improved after therapy (p<0.01). No difference in motor performance as evaluated by UPDRS was reported. SPM analysis showed a significant increase of perfusion (p < 0.0001) in bilateral cingulate, and frontal regions after ChEIs. Our data confirm the efficacy of ChEIs in the treatment of dementia associated with PD mainly on attention and executive functions, and the functional findings indicate that this cognitive improvement could be associated with a sort of pharmacological frontal "re-afferentation".

From mild cognitive impairment to dementia: a prevalence study in a district of Tuscany, Italy.

OBJECTIVE: A door-to-door two-phase study was designed in order to estimate the prevalence of cognitive deficit amongst the residents of a district in Tuscany (central Italy). Identification of cases with mild cognitive impairment (MCI) was given high priority, because this condition has been suggested as a term for the boundary area between normal aging and dementia. METHODS: Of the 1600 subjects who completed the screening phase, 354 scored under the cut-off point of the Mini Mental State Examination and Clinical Dementia Rating and were investigated by means of a standardized diagnostic protocol. RESULTS: The prevalence of MCI and age-related cognitive decline was 4.9 and 9.3%, respectively; low levels of education significantly increased the risk of these conditions. The prevalence of dementia over age 65 was 6.2%, with a significant risk association with age. In our population, Alzheimer's disease was the most frequent type of dementia (prevalence rate 4.2%) and increased risk depending on age, sex and education has been found. CONCLUSIONS: Our findings are somewhat similar to previous studies. Further epidemiological and longitudinal studies are warranted to identify which diagnostic category is more predictive for dementia.

A non-syndromic hearing loss caused by very low levels of the mtDNA A3243G mutation.

We described a patient with progressive non-syndromic hearing loss (NSHL) harboring the A3243G mutation in the mitochondrial DNA (mtDNA). Muscle biopsy showed scattered ragged-red, cytochrome c oxidase negative fibers, whereas the biochemical analysis of the mitochondrial respiratory chain complexes was normal. Restriction fragment length polymorphism (RFLP) analysis showed A3243G mtDNA transition, present at very low in patient's muscle (3%) and in urinary sediments (1%), and not detectable in blood and buccal mucosa. The patient was submitted to a bilateral cochlear implantation with post-operative excellent hearing and communicative outcomes. Our findings indicate that A3243G mutation may be responsible both for SHL and NSHL, may be depending on the levels of mutated mtDNA. Patients with hearing loss due to mtDNA mutations should be considered as good candidates for cochlear implantation.

Autosomal dominant external ophthalmoplegia and bipolar affective disorder associated with a mutation in the ANT1 gene.

The authors report on a family with dominantly inherited progressive external ophthalmoplegia and a diagnostic and statistical manual (fourth revised edition) diagnosis of bipolar psychiatric disorder in several members. Skeletal muscle biopsy from the proposita showed decreased cytochrome c oxidase staining, several ragged-red fibers, and multiple mtDNA deletions. The authors identified a missense mutation (leucine 98-->proline) in the adenine nucleotide translocator 1 gene. The presence of bipolar affective disorder expands the phenotype of adenine nucleotide translocator 1 allelic variants.

Extended thymectomy in myasthenia gravis: a team-work of neurologist, thoracic surgeon and anaesthesist may improve the outcome.

OBJECTIVE: We reviewed our overall experience on 163 patients, affected by myasthenia gravis, who underwent thymectomy between 1976 and 1998. A comparison between the oldest series of 72 patients (January 1976-December 1992), referred by various neurologists and operated on through different approaches, and the last 91 patients (January 1993-December 1998), taking part in a strict diagnostic-therapeutical programme, was made. METHODS: Anagraphic data, duration of symptoms, the surgical approach, necessity of respiratory assistance, the hospital stay, histopathological findings, preoperative and postoperative Osserman classification, as well as medications, were globally analyzed and then compared in the two groups. RESULTS: Significant differences in the length of hospitalization (8.7 days vs. 4.2 days; P=0.00001) and in the prolonged intubation rate (18 vs. 0; P<0.000001) were observed in the most recent series. Patients in the pre-operative Osserman stage I and operated on in the second period had a higher complete remission rate at the univariate analysis (P<0.001 and P<0.0001, respectively). At the multivariate analysis the only parameter which affected the outcome was to be operated on in the second period (P<0.01). CONCLUSIONS: Our experience confirms the role of the extended thymectomy in the treatment of myasthenia gravis. Whenever an extended thymectomy was performed through a complete sternotomy it was a quick procedure, with short hospitalization and acceptable cosmetic results. A careful pharmacological control of the myasthenic symptoms and the presence of team-work among neurologist, thoracic surgeon and anaesthesist in the peri-operative setting reduce the incidence of complications and might increase the efficacy of the thymectomy.

Circulating levels of allopregnanolone, an anticonvulsant metabolite of progesterone, in women with partial epilepsy in the postcritical phase.

PURPOSE: Several lines of evidence indicate that there exists a relation between ovarian hormones and epilepsy. Estrogens decrease seizure threshold and increase brain excitability, whereas progesterone has an inhibitory effect and reduces epileptiform activity. Recently considerable interest has turned to neuroactive steroids, a group of progesterone metabolites, as endogenous modulators of excitability of the central nervous system (CNS). Their ability to alter neuronal firing rapidly occurs through interaction with gamma-aminobutyric acid (GABA) A receptor complex. In a previous experience, serum allopregnanolone (3alpha-OH-5alpha-pregnan-20-one) levels were measured in 15 women with partial epilepsy in the intercritical phase, and no significant differences were found between patients and control subjects. METHODS: To find out if there are changes in serum allopregnanolone levels after epileptic seizure, blood samples were drawn immediately, 15 min, and 6 h after a seizure in seven fertile females with partial epilepsy. RESULTS: The most interesting finding is that allopregnanolone increases in serum during the first 15 min after partial seizures (p < 0.05) and decreases after 6 h. CONCLUSIONS: These data are consistent with a role for allopregnanolone in the control of neuronal excitability and seizures.

Long-term interferon beta-1b therapy for MS: is routine thyroid assessment always useful?

BACKGROUND: The authors previously reported on the development of thyroid dysfunction and autoimmunity during 1-year treatment of patients with MS with interferon-beta 1b (IFN beta-1b). OBJECTIVE: To evaluate the evolution of incident thyroid disease and the possible development of more thyroid disease during longer term therapy. PATIENTS: The authors studied 31 patients (aged 34 +/- 7 years; 21 women) with relapsing-remitting MS during 3 years of IFN beta-1b treatment. Systematic thyroid assessment was performed every 3 or 6 months, depending on the development of thyroid disease. RESULTS: After the first year of IFN beta-1b treatment, no further cases of thyroid disease were observed. Among the six patients with early incident subclinical hypothyroidism, thyroid dysfunction persisted only in those with baseline autoimmune thyroiditis (n = 2). The three patients who developed transient hyperthyroidism remained euthyroid throughout the treatment course. A positive autoantibody titer was continually detected in only two out of five patients without baseline autoimmunity. CONCLUSIONS: The risk of thyroid disease seems related to IFN beta-1b treatment during the first year only, particularly in patients with preexisting thyroiditis. Furthermore, incident thyroid dysfunction is generally transient and mild in degree. Indeed, we recommend a routine systematic thyroid assessment only in patients with baseline thyroiditis. During the first year of therapy, serum thyroid-stimulating hormone measurement should suffice as first line test; a systematic thyroid assessment is only useful for those patients with incidental and persistent dysfunction. Further studies with many patients will be necessary to confirm our suggestions as broad clinical guidelines.

Abnormal H-Tfam in a patient harboring a single mtDNA deletion.

We report on a patient suffering from a progressive mitochondrial disorder characterized by ocular myopathy, exercise intolerance, and muscle wasting. Morphological examination of muscle biopsy showed increased variability in fiber size and scattered ragged-red fibers. Analysis of muscle mitochondrial DNA by Southern blot and PCR revealed a heteroplasmic single deletion of 4100 base pairs, located between nucleotide positions 8300 and 12,400. Western blot analysis showed high levels of the human mitochondrial transcription factor A (Tfam). Interestingly, we also detected an additional Tfam product, of approximately 22 kDa. This is the first case in which a qualitatively abnormal Tfam has been found to be associated with a mitochondrial disorder in humans.

Is lithium able to reverse neurological damage induced by vinca alkaloids? (Short communication).

Lithium (Li) actively antagonises the inhibiting action of vinca alkaloids on human leukocyte chemotaxis; it proved to be related to the activation of microtubular system, possibly mediated by its inhibiting effect on cyclic AMP. Vinca alkaloids induce peripheral neuropathy and muscle damage. The molecular basis of this neurotoxicity has not been fully explained, but a possible role of neurofibrillary degeneration has been reported. We studied both in animals and in humans, whether Li is able to antagonise vinca alkaloid neurotoxicity.

T-cell interleukin-6 receptor binding in patients with myasthenia gravis.

Myasthenia gravis (MG) is a T-cell-dependent and antibody-mediated autoimmune disease of the neuromuscular junction, in which the cytokine network may be deranged. Specific receptors for interleukin (IL)-6, a cytokine with several effects on the neuroimmune system, have been found on human lymphocytes. The aim of the present study has been to assay IL-6 binding on peripheral blood T cells from MG patients. We found that T cells from MG patients have significantly more IL-6 receptors than those from controls (Bmax: 334 +/- 6 vs 251 +/- 4 (mean +/- SEM) receptors/cell). Such IL-6 binding sites are of the same type in patients and healthy subjects (Kd: 26.5 +/- 0.7 vs 25.7 +/- 0.9 (mean +/- SEM) pM). The enhanced T-cell interleukin-6 binding is due to an increased number of interleukin-6 receptors on T-helper lymphocytes. These results are discussed in terms of MG immunopathogenesis, since it has been reported that activated T cells have increased amounts of IL-6 receptors.

Mitochondrial tRNA(Cys) gene mutation (A5814G): a second family with mitochondrial encephalopathy.

We report an Italian family with maternally inherited encephalomyopathy including progressive external ophthalmoplegia, seizures, and neurophysiological evidence of brainstem dysfunction. Mitochondrial DNA analysis showed a heteroplasmic point mutation at position 5814 in the tRNA gene for cysteine (A5814G), previously reported in a 5-year-old girl of Portuguese origin. The mutation was very abundant (> 95%) in both muscle and blood from the proposita and was present in lower proportions (average 85 +/- 6%) in blood from three less severely affected maternal relatives. This observation confirms pathogenicity for the A5814G mutation.

Catamenial epilepsy, progesterone and its metabolites.

This study was undertaken to determine plasma allopregnanolone (3alpha-hydroxy-5alpha-pregnan-20-one, A-PREG) and pregnanolone (3alpha-hydroxy-5beta-pregnan-20-one, PREG) concentrations in the luteal phase (22nd to 24th day of the ovarian cycle) in 15 women with partial epilepsy and catamenial exacerbation of the seizures in the intercritical phase and in 15 healthy women matched for age in order to determine if an impaired metabolism of 3alpha-hydroxymetabolites of progesterone (P) occurs in this convulsive disorder. No significant differences between the two groups were found with respect to the mean plasmatic A-PREG and PREG levels. A significant correlation was found instead between P and A-PREG or PREG concentrations.

Circulating levels of anticonvulsant metabolites of progesterone in women with partial epilepsy in the intercritical phase.

The 3alpha-hydroxy metabolites of progesterone (P), 3alpha-hydroxy-5alpha-pregnan-20-one (allopregnanolone, A-PREG) and 3alpha-hydroxy-5beta-pregnan-20-one (pregnanolone, PREG), have been found to be among the most potent ligands of gamma-aminobutyric (GABA)-A receptors; in experimental animals, they have been found to have anxiolytic, hypnotic and anticonvulsant effects. Similar to those of the benzodiazepines and barbiturates that interact with GABA-A receptors. The present study was undertaken to determine plasma A-PREG and PREG concentrations in the luteal phase in women with partial epilepsy, in order to determine if an impaired metabolism of P occurs in this convulsive disorder. We measured plasma P, A-PREG and PREG levels in 15 women with partial epilepsy in the intercritical phase, and in 15 age-matched healthy women, during the luteal phase of the ovarian cycle (22nd-24th day). The mean plasma +/- S.E. A-PREG levels (three blood samples) were 0.7 +/- 0.6 ng/ml in the epileptic women and 0.5 +/- 0.2 ng/ml in controls, with no significant difference between the two groups (p = NS); the PREG levels were also similar (1.4 +/- 1 ng/ml and 1 +/- 1.1 ng/ml, respectively: p = NS). A significant correlation was found between P levels and both A-PREG and PREG levels (r = 0.72, p < 0.001 and r = 0.79, p < 0.001, respectively). There were no significant differences between the two groups in terms of serum adrenocorticotropic hormone, cortisol, dihydroepiandrosterone-sulfate, follicle stimulating hormone, prolactin, luteinizing hormone or estradiol levels.

Cryoglobulinemic peripheral neuropathy: neurophysiologic evaluation in twenty-two patients.

The aim of this study was to evaluate the frequency and degree of peripheral neuropathy in 22 consecutive patients with mixed cryoglobulinemia, whether symptom-free or with subjective neurological symptoms. Electrophysiological investigations were carried out and a biopsy of the sural nerve was performed in six patients. Peripheral neuropathy of the lower limbs was demonstrated, which was mostly sensory and light or moderate in 86% of cases (19 patients). F-Wave and H-reflex recordings were found to be the most reliable methods; in 77% of cases, they were abnormal (17 patients). Using somatosensory evoked potentials, we were able to exclude simultaneous central nervous system involvement in 10 patients.