Utility of a patient survey in identifying fluctuations in early stage Parkinson's disease.

Motor and non-motor fluctuations are well known sequelae of dopaminergic therapies for Parkinson's disease (PD), particularly during the advanced stages. However, the prevalence of fluctuations early in the treatment course has been less well recognised and may be missed clinically if not specifically probed. We examined the used of a survey for this purpose. Patients to be surveyed were recruited by neurologists and geriatricians at 20 Australian centres. Patients had a diagnosis of idiopathic PD with a duration of fewer than 5 years and were considered by their treating physician to be non-fluctuating or had no change in their treatment plan in the prior 6 months. Patients, with or without assistance, completed a 19-item wearing-off questionnaire to assess the presence of motor and non-motor fluctuations that indicated early wearing-off. Investigators assessed the usefulness of the questionnaire in detecting fluctuations and guiding PD treatment. Of 105 patients recruited, 92 were eligible for analysis. There were 56 (61%) identified as having fluctuations. Patients with wearing-off were younger (mean 67 vs 72 years), and more likely to have had PD for more than 3 years. About half the patients (49%) were able to complete the questionnaire independently. Clinicians perceived the questionnaire as useful for detecting fluctuations and adjusting treatment. A simple and easily administered wearing-off questionnaire may be useful in the early detection of fluctuations in PD patients and assist in guiding therapy.

AUStralian study of titration to effect profile of safety (AUS-STEPS): high-dose gabapentin (neurontin) in partial seizures.

PURPOSE: To evaluate the safety, tolerability, efficacy, and impact on quality of life of gabapentin (Neurontin; GBP) as adjunctive therapy in patients with refractory partial seizures. METHODS: AUS-STEPS was an open-label, multicenter, prospective study in patients experiencing partial seizures who were inadequately controlled with one to three concurrent antiepileptic drugs (AEDs). GBP treatment was titrated to a maximum of 4,800 mg/day, over a treatment period of 24 weeks, to achieve an efficacious and tolerable dosage. Efficacy was assessed by seizure-frequency data. Quality of life was evaluated by using the QOLIE-10 questionnaire, and safety was assessed by adverse-event reports and clinical laboratory findings. RESULTS: A total of 176 patients received treatment with GBP, with 174 evaluable for intention-to-treat (ITT) efficacy analysis. A reduction of >50% in overall seizure frequency was observed in 93 patients (53%). There was a small (4.6%) overall improvement in QOLIE-10 score. The most frequent adverse events were dizziness (31%), fatigue (29%), somnolence (27%), headache (21%), and ataxia (20%), with no major increase seen in adverse events necessitating discontinuation as the dose of GBP was titrated upward. CONCLUSIONS: This study indicates that patients with partial epilepsy may be effectively treated with GBP at dosages of < or =4,800 mg/day, without altering the safety profile of the drug.

A novel syndrome of episodic muscle weakness maps to xp22.3.

We describe a family with a novel disorder characterized by episodic muscle weakness and X-linked inheritance. Eight males in three generations demonstrate the characteristic features of the disorder. Episodes of severe muscle weakness are typically precipitated by febrile illness and affect the facial and extraocular musculature, as well as the trunk and limbs, and resolve spontaneously over a period of weeks to months. Younger members of the family are normal between episodes but during relapses show generalized weakness, ptosis, and fluctuations in strength. In some cases, fatigability can be demonstrated. The proband has late-onset chronic weakness and fatigability. The clinical phenotype has features suggestive both of the congenital myasthenic syndromes and of ion-channel disorders such as the periodic paralyses. We have localized the responsible gene to chromosome Xp22.3, with a maximum two-point LOD score of 4. 52 at a recombination fraction of.0, between OACA2 and DXS9985.

Double-blind, placebo-controlled, crossover study of lamotrigine in treatment-resistant generalised epilepsy.

PURPOSE: Lamotrigine (LTG) is recognised as effective add-on therapy for focal epilepsies, but this is the first double-blind, placebo-controlled, crossover study in treatment-resistant generalised epilepsy. METHODS: The study consisted of 2 x 8-week treatment periods followed by a 4-week washout period. Patients received doses of either 75 or 150 mg daily, depending on their concomitant antiepileptic drugs (AEDs). Long-term continuation was offered at the end of the study with open-label LTG. RESULTS: Five centres in Australia recruited 26 patients who were having absence, myoclonic, or generalized tonic-clonic seizures or a combination of these. Twenty-two patients completed the study. There was a significant reduction in frequency of both tonic-clonic and absence seizure types with LTG. A 350% decrease in seizures was observed for tonic-clonic seizures in 50% of cases and for absence seizures in 33% of evaluable cases. Rash was the only adverse effect causing discontinuation. Twenty-three of 26 opted for open-label LTG, with 20 still receiving LTG for a mean of 26 months. In these 20, 80% had > or =50% seizure reduction and five (25%) were seizure free. CONCLUSIONS: This study shows that LTG is effective add-on therapy in patients with refractory generalised epilepsies. Statistically significant reduction in seizures in both absence and tonic-clonic seizure types was seen even with low doses of LTG.

A double-blind, placebo-controlled crossover study of vigabatrin 2 g/day and 3 g/day in uncontrolled partial seizures.

The efficacy and tolerability of vigabatrin as add-on therapy was assessed in patients with uncontrolled partial seizures. Ninety-seven patients entered this seven-centre, double-blind, placebo-crossover study. Vigabatrin (2 g or 3 g) or placebo was administered daily. Vigabatrin was well-tolerated and did not cause clinically significant adverse drug effects when added to established anticonvulsant therapy. No significant differences were observed between dose groups for the overall incidence of adverse events, although drowsiness and visual disturbances (diplopia, ataxia, visual abnormalities) showed a dose-related increase with vigabatrin treatment. The results of this study indicate that vigabatrin, given in a daily dose of either 2 g or 3 g is significantly more effective than placebo in reducing seizure frequency among patients with partial seizures.

Neurocysticercosis: an under-recognized cause of neurological problems.

Neurocysticercosis is an uncommon, and under-recognized condition in Australia. Changes in immigration patterns may lead to a rising prevalence in this country. Epilepsy is the most common presentation, but it has many other variable forms of neurological manifestations. Eight cases are described, all in immigrants from Eastern Europe, Asia or Central America; the disease was presumably acquired before arrival in Australia. Six patients had symptoms for two to 30 years before the diagnosis was made and, in some cases, the first neurological manifestations appeared decades after initial infection. In patients with active disease a successful outcome followed therapy with praziquantel and corticosteroids. We advise that all patients requiring treatment be admitted to hospital for corticosteroid and anticonvulsant therapy to minimize the clinical deterioration which may result from therapeutic destruction of larvae.

Inhibition of allergic encephalomyelitis by the iron chelating agent desferrioxamine: differential effect depending on type of sensitizing encephalitogen.

Induction of experimental allergic encephalomyelitis (EAE) in Lewis rats by injection of guinea pig (GP) spinal cord homogenate (SCH) plus adjuvant (SCH-CFA) can be inhibited by treatment with the iron chelating agent desferrioxamine (DFOM). Interestingly, induction of EAE with purified myelin basic protein (BP-CFA) is not inhibited with DFOM. This dichotomy does not appear to be due to any quantitative differences in the two inocula since minimal clinical EAE produced by threshold levels of BP is not inhibited with DFOM. Passive EAE is not inhibited irrespective of the type of encephalitogen used to sensitize the donors. This suggests that the inhibitory effect of DFOM is acting on the afferent limb of the immune response to SCH-CFA. Injection of BP-CFA and SCH-CFA into the same site, mixing BP with central nervous system (CNS) lipids, or incorporating BP into liposomes, all induce EAE which can be partially inhibited by treatment with DFOM. These results support the hypothesis that the close association of lipids with the encephalitogen (i.e. BP) in SCH required extensive lipid breakdown before adequate antigen presentation can occur, and it is at this level that DFOM exerts its inhibitory effect.

Cerebral infarction due to presumed haemodynamic factors in ambulant hypertensive patients.

The role of haemodynamic factors in the pathogenesis of cerebral infarction is unclear. Watershed or distal field infarction is most often caused by haemodynamic mechanisms. Watershed cerebral infarcts can now be identified in stroke survivors using CT scanning. The clinical findings are presented of 14 patients with cerebral infarction in whom haemodynamic factors contributed to the stroke. Evidence for this diagnosis includes (i) a history of posture-related or exercise-induced syncopal attacks or neurological deficits before and in some cases after the stroke, (ii) the demonstration of watershed or distal field infarction on CT scan, (iii) commencement of symptoms after increase in antihypertensive medications, and (iv) improvement following reduction of treatment. Regional cerebral hypoperfusion may be a more common cause of cerebral infarction than is generally thought. Particular care should be exercised when potent antihypertensive medication is prescribed for elderly hypertensive patients.

Immunoglobulin deficient rats as donors and recipients of effector cells of allergic encephalomyelitis.

Lewis rats, treated from birth with a rabbit anti-rat IgM antiserum are B-cell and immunoglobulin deficient. When sensitized with myelin basic protein (BP) and complete Freund's adjuvant (CFA), these rats do not make detectable antibodies to BP, nor do they develop clinical or histopathological evidence of allergic encephalomyelitis (EAE). We show here that transfer of anti-BP antibody containing serum to BP sensitized Ig deficient rats results in subsequent development of EAE. We also demonstrate that BP sensitized Ig deficient rats which do not develop EAE, nevertheless generate effector cells capable of transferring disease, and thus specific T-cell function is not inhibited by the anti-Ig treatment. Finally, Ig deficient rats were shown to be perfectly adequate recipients of passively induced EAE.

Immunoregulation of passively induced allergic encephalomyelitis.

Experimental allergic encephalomyelitis (EAE) can be readily induced passively by transfer of lymphocytes from neuroantigen immunized rats to naive recipients. This passively induced disease runs an acute, monophasic, self-limiting course, much the same as is usually seen in actively induced diseases. Here we examine the mechanisms regulating passive EAE. We report that splenectomy, thymectomy, and increasing age of recipients, manipulations which have been reported to influence recovery from actively induced EAE, have no effect on passively induced disease. EAE effector cells are not inactivated when transferred into recipients that have been actively sensitized and are beginning their recovery from clinical signs; this being a time when recovery associated suppressor cells are thought to be present. Finally, in the absence of suppressor T cells in both the recipient and in the transfer cell population, recovery from passive EAE still occurs. We conclude that suppressor T cells play no role in regulating passively induced EAE.

The fate of neonatally injected effector cells of allergic encephalomyelitis.

Lymphocytes from rats sensitized with basic protein (BP) plus complete Freund's adjuvant (CFA), which produce allergic encephalomyelitis when transferred to adult recipients, fail to induce disease when transferred to 3- to 5-day-old neonatal rats. The transferred cells do, however persist in the recipients and can be revealed by actively challenging with BP-CFA later in adult life. Challenge leads to a significantly earlier onset of disease than is seen in control animals. We report here that the cells are long lived and persist in the recipients for at least 9 months. The cells can be demonstrated in the spleen and lymph nodes of recipient animals and can be activated by homologous and cross-reacting encephalitogenic antigenic preparations but not by antigen in nonencephalitogenic forms. These neonatal recipients, which carry autoimmune effector cells asymptomatically for prolonged periods, may provide a useful model for advancing our understanding of immunoregulatory events in this experimental demyelinating disease as well as the human demyelinating disease multiple sclerosis.

Reactivation of allergic encephalomyelitis by means of allogeneic confrontation.

Lewis rats recovered from experimental allergic encephalomyelitis (EAE) are resistant to active reinduction of disease. (DA X Lewis)F1 hybrids behave in an identical fashion. The induction of a graft versus host (GVH) reaction in EAE convalescent (DA X Lewis)F1 rats, by injection of normal parental (Lewis) lymphocytes, precipitates a second episode of EAE in a proportion of rats. This secondary episode of EAE can be induced by injection of parental cells either systemically (intravenously) or locally (subcutaneously in the foot). A host versus graft (HVG) reaction does not reactivate EAE in the convalescent host. The observed effect is probably due to reactivation of EAE effector cells following the extensive nonspecific proliferation of host lymphoid cells which is a feature of GVH reactivity.

Experimental allergic encephalomyelitis: effect of neonatal exposure to neuroantigen or neuroantigen immune cells on subsequent reactivity as adults.

Neonatal Lewis rats are resistant to both active induction of EAE with neuroantigen and passive induction by transfer of immune cells. Actively sensitized neonates are, as adults, resistant to further active induction of disease, but are susceptible to passive induction with immune cells. Passively sensitized neonates are susceptible to active and passive disease as adults. In fact, actively sensitized adult animals which had received immune cells as neonates develop EAE much sooner than control animals, suggesting a memory response and the persistence of the transferred cells in the host. The cells persist for at least six months and these animals might be considered to be inapparent carriers of autoimmune disease.

Spatial contrast sensitivity in patients with multiple sclerosis.

Contrast sensitivity tests a basic visual function which is not examined by conventional visual acuity testing or visual evoked responses. It is frequently abnormal in patients with multiple sclerosis. The lack of relationship between VERs and SCSF implies that contrast sensitivity measures aspects of the visual system not examined by the conventional electrophysiological technique, probably visual function situated beyond the anterior visual pathway. It is therefore a useful complementary diagnostic test for patients with multiple sclerosis. Both VER and spatial contrast sensitivity separately detect a high proportion of patients with multiple sclerosis. When used in combination, the two techniques give a yield which approaches 100%. Contrast sensitivity testing as used here is cumbersome and time-consuming. Use of fewer spatial frequencies and/or adaptation of VER techniques for estimation of a contrast threshold may be more applicable for clinical use.

Ophthalmological complications of cryptococcal meningitis.

Two patients with cryptococcal meningitis associated with ophthalmological complications are described. One patient developed a cryptococcal fundal lesion which disappeared during chemotherapy. Chronically raised intracranial pressure was associated with a visual field defect. This resolved with repeated lumbar punctures. The second patient developed visual deficits secondary to papilloedema and responded to optic nerve decompression. In both cases CT scanning demonstrated swelling of the optic nerves. In the second patient this regressed after decompression. A review of the variety of the ophthalmological complications of cryptococcal meningitis and their prevalence is presented. The risk of developing severe visual disability is assessed.

Anticonvulsant effects on the memory performance of epileptics.

The effects of different drugs on memory function in epileptic patients were examined. Patients had clinically normal cognitive function, above average IQs and infrequent seizures. Compared with pre-treatment evaluation, treatment with phenytoin, but not with carbamazepine or sodium valproate, resulted in impaired memory performance after three months of treatment. Switching patients previously treated with phenytoin to carbamazepine resulted in an improvement in memory performance compared with that of patients remaining on phenytoin. Switching patients from carbamazepine to sodium valproate did not result in any change in performance compared with that of those remaining on carbamazepine. The results of these experiments suggest that phenytoin, but not carbamazepine or sodium valproate, causes impaired memory performance. The nature of the memory dysfunction and its clinical implications are discussed.

Anticonvulsants, folic acid and memory dysfunction in epileptics.

The results of a survey of 116 epileptic patients treated by monotherapy with phenytoin, carbamazepine and sodium valproate are described. No significant correlations were found between memory performance and serum anticonvulsant levels. However, correlations were found between memory performance and levels of red cell folate. The hypothesis that phenytoin may impair memory performance through the reduction of folate is discussed.

A clinical and electrophysiological study of neurogenically induced winging of the scapula.

Four cases of neurogenically induced winging of the scapula are described. Systematic clinical evaluation enabled the affected nerve or nerves to be defined in each case, particular attention being directed to the presence or absence of deformity at rest, the direction of rotation of the winging scapula, and the movement of the arm that produced maximal scapular winging. EMG studies were performed on all 4 cases and serial spinal accessory nerve conduction studies on the 2 patients with involvement of this nerve. Both techniques proved useful adjuncts to clinical evaluation and provided confirmatory diagnostic information. The accessory nerve conduction studies were of further value in assessing the extent and type of neural damage, the rate of recovery and the prognosis.

The effects of anticonvulsants on memory function in epileptic patients: preliminary findings.

Recent studies have indicated that at least one anticonvulsant has a deleterious effect on memory but the evidence for other major anticonvulsants is conflicting. The memory function of 15 newly diagnosed epileptic patients was examined before and after monotherapy with phenytoin, carbamazepine or sodium valproate. In addition, 17 epileptic patients taking phenytoin alone were examined. No effect on memory function after 3 months of treatment with any one of the 3 drugs was found. No correlation was found between the serum phenytoin levels and performance on the memory tests. Whether the above anticonvulsants are entirely free of effect on memory function cannot be decided until a larger group of patients is studied and until different, perhaps more subtle, aspects of memory are examined.