Mutations in CAV3 cause mechanical hyperirritability of skeletal muscle in rippling muscle disease.

Hereditary rippling muscle disease (RMD) is an autosomal dominant human disorder characterized by mechanically triggered contractions of skeletal muscle. Genome-wide linkage analysis has identified an RMD locus on chromosome 3p25. We found missense mutations in positional candidate CAV3 (encoding caveolin 3; ref. 5) in all five families analyzed. Mutations in CAV3 have also been described in limb-girdle muscular dystrophy type 1C (LGMD1C; refs. 6,7), demonstrating the allelism of dystrophic and non-dystrophic muscle diseases.

Increase of CD8+ T-effector memory cells in peripheral blood of patients with relapsing-remitting multiple sclerosis compared to healthy controls.

CCR7 and CD45RA expression on CD4+ and CD8+ T-cells in blood (PB) of 16 patients with multiple sclerosis (MS) and 16 healthy controls and cerebrospinal fluid (CSF) of 10 patients suffering from MS were analysed by flow cytometric measurements. T-cells were divided by their distinct homing potentials and effector-functions in three groups: naïve T-cells (CCR7+, CD45RA+), central memory T-cells (TCM) (CCR7+, CD45RA-) and effector memory T-cells (TEM) (CCR7-, CD45RA-). There was a significant increase of CD8+ TEM-cells in PB of MS patients compared to healthy controls, indicating systemic immune activation. Further we found a relative depletion of CD8+ TEM-cells in CSF of MS patients compared to matching blood samples, suggesting that these cells represent the effector arm of the immune response and infiltrate the brain tissue at the sites of inflammation.

Creatine therapy in myophosphorylase deficiency (McArdle disease): a placebo-controlled crossover trial.

OBJECTIVE: To determine whether treatment with creatine can improve exercise intolerance in myophosphorylase deficiency (McArdle disease). DESIGN: Double-blind, placebo-controlled crossover study with oral creatine monohydrate supplementation. PATIENTS: Nine patients with biochemically and genetically proven McArdle disease were treated. INTERVENTION: Five days of daily high-dose creatine intake (150 mg/kg body weight) were followed by daily low-dose creatine intake (60 mg/kg). Each treatment phase with creatine or placebo lasted 5 weeks. MAIN OUTCOME MEASURES: The effect of treatment was estimated at the end of each treatment phase by recording clinical scores, ergometer exercise test results, phosphorus 31 nuclear magnetic resonance spectroscopy, and surface electromyography. RESULTS: Of 9 patients, 5 reported improvement of muscle complaints with creatine. Force-time integrals (P =.03) and depletion of phosphocreatine (P =.04) increased significantly during ischemic exercise with creatine. Phosphocreatine depletion also increased significantly during aerobic exercise (P =.006). The decrease of median frequency in surface electromyograms during contraction was significantly larger (P =.03) with creatine. CONCLUSION: This is the first controlled study indicating that creatine supplementation improves skeletal muscle function in McArdle disease.

Phenotypic variability in rippling muscle disease.

OBJECTIVE: To characterize the phenotype of hereditary rippling muscle disease (RMD) and to report the results of genetic linkage studies. BACKGROUND: RMD is a rare autosomal-dominant inherited muscle disorder. Individuals complain of muscle stiffness, exercise-induced muscle pain, and cramp-like sensations. The characteristic feature of RMD is increased mechanical muscle irritability, which is electrically silent in electromyographic examinations. METHODS: Forty-six individuals from two unrelated German kindreds with RMD were examined. Linkage analysis to the RMD locus on chromosome 1q41-q43 was performed. RESULTS: In kindred A, 15 individuals from four generations, and in kindred B, four individuals from three generations had clinical features of RMD. The most consistent clinical findings were percussion-induced rapid muscle contractions (PIRCs) and muscle mounding, which were present in all 19 affected individuals. Only 12 individuals exhibited muscle rippling, indicating that rippling is not always present in RMD. Twelve of 19 individuals had muscle-related complaints, primarily exertional cramps and stiffness. The mean age at the onset of complaints was 22 years (range, 5 to 54 years). Seven of 19 individuals showed only mechanical-induced muscle irritability but did not have muscular symptoms. Genetic analysis excluded linkage to the RMD locus on chromosome 1q4 in both kindreds. CONCLUSIONS: The phenotype of RMD is variable but generalized PIRCs are the most obvious and reliable clinical feature of RMD. Diagnostic criteria of RMD should include generalized PIRCs in addition to muscle mounding, rippling, and creatine kinase elevation.

Hemisensory impairment in patients with complex regional pain syndrome.

The purpose of the present study was to investigate the extent and quality of sensory impairment and their relation to pain characteristics and movement disorders in patients suffering from complex regional pain syndrome (CRPS) type I. Neurological testing was performed independently by two examiners in 24 patients with CRPS type I. In eight patients (33%), a hemisensory impairment with decreased temperature and pinprick sensation ipsilateral to the limb affected by CRPS could be observed. In four patients (17%), a sensory deficit in the upper quadrant of the body could be demonstrated and in eight patients (33%), sensory impairment was limited to the limb affected by CRPS. Mechanical allodynia and mechanical hyperalgesia could be observed in a higher percentage of patients with hemisensory deficit or sensory impairment in the upper quadrant (92%), than in those patients with sensory impairment limited to the affected limb (17%) (P < 0.005). In patients with left-sided CRPS, sensory abnormalities in the upper quadrant or hemisensory impairment were more frequently demonstrated (77%) than in patients with right-sided CRPS (18%) (P < 0.005). There was a high correlation (92%) for the sensory findings between the two examiners, and hemisensory abnormalities were stable over a period of 3-6 months in all six patients with repeated examinations. Motor impairment (contractures, weakness, tremor or difficulties in initiating movement) could be observed in a higher percentage in patients with sensory abnormalities in the upper quadrant or hemisensory impairment (83%) than in patients with sensory impairment limited to the affected limb (42%) (P < 0.05) and was significantly correlated with allodynia/hyperalgesia (P < 0.005). The results demonstrated that sensory deficits in patients with CRPS, frequently extend past the painful area of the affected limb. The increased frequency of mechanical allodynia and movement disorders in patients with hemisensory impairment or sensory deficits in the upper quadrant, might indicate that central mechanisms are involved in the pathogenesis of CRPS in these patients.

Impaired aerobic glycolysis in muscle phosphofructokinase deficiency results in biphasic post-exercise phosphocreatine recovery in 31P magnetic resonance spectroscopy.

Using 31P magnetic resonance spectroscopy, energy metabolism in calf muscles of two patients with biochemically and genetically proven muscular phosphofructokinase deficiency, and an asymptomatic heterozygote was monitored during isometric foot plantarflexion performed under aerobic and anaerobic conditions and in the aerobic recovery phases. In the heterozygote only a moderate alteration from normal was found in terms of an elevated ATP demand during exercise. In the homozygote, hexose phosphates, indicated as phosphomonoesters, increased dramatically during contraction. Phosphomonoester accumulation resulted in consumption of free inorganic phosphate (P(i)). During ischemic exercise the absence of glycolytic ATP formation resulted in a linear time course of phosphocreatine breakdown and a moderate alkalinization. During the recovery, phosphocreatine resynthesis showed a biphasic time course, indicating that mitochondrial function itself was not directly affected. At first glance, the early depletion of P(i) below initial resting levels and the rate of phosphate splitting from sugar phosphates seemed to become the limiting factor for the rate of the oxidative phosphorylation and creatine kinase reaction. However, the actual concentrations of P(i) and ADP estimated at the onset of delay were too high to exclusively explain the dramatic delay in PCr resynthesis. For this reason, a reduced turnover of the citric acid cycle was assumed, which was caused by the complete absence of glycolysis in PFK deficiency patients. Furthermore, results from PFK deficiency patients were compared with previous findings from myophosphorylase deficiency patients in the literature.

Immunomodulatory effects of interferon-beta-1b in vivo: induction of the expression of transforming growth factor-beta1 and its receptor type II.

The mechanisms by which interferon-beta-1b (IFNbeta-1b) acts in the treatment of patients with multiple sclerosis (MS) are not completely known. A total of 10 MS patients were treated with 8 million units of IFNbeta-1b every other day. Compared to baseline and control group the expression of TGFbeta-1-mRNA by PBMC was persistently increased at week 6, month 3 and month 6 (p < or = 0.04), that of the TGFbeta-1 receptor type II from day 5 up to month 6 (p < 0.01). The mRNA and protein expression of tumor necrosis factor-alpha (TNFalpha)-receptor (55 kDa) was only temporarily elevated at the beginning of the therapy. Serum levels of sVCAM were increased during the whole time of treatment (p < 0.01). The CD8CD38 lymphocyte subpopulation was continuously elevated from day 5 up to month 6 (p < 0.01). No persistently significant changes were demonstrable concerning the percentage of total CD4, CD8, CD19 or in CD4 subpopulations (CD4CD29, CD4CD45RA). The present data suggest that IFNbeta-1b induces the expression of TGFbeta-1- and TGFbeta-R-II-mRNA by PBMC and increases levels of sVCAM-1 and of circulating activated CD8 cells (CD8CD38) in serum. These might be other mechanisms by which IFNbeta-1b mediates its positive effects in the treatment of MS patients.

Corticosteroids induce expression of transforming-growth-factor-beta1 mRNA in peripheral blood mononuclear cells of patients with multiple sclerosis.

The mechanisms by which corticosteroids act in the treatment of an acute relapse in multiple sclerosis (MS) are not completely known. We investigated the mRNA and protein expression of transforming-growth-factor-beta1 (TGFbeta1), a cytokine with anti-inflammatory and immunosuppressive potentials, in peripheral blood mononuclear cells (PBMC) and serum of 10 patients with an acute relapse of MS before, during and after the treatment with 500 mg prednisolone daily over 5 days. The expression of TGFbeta1-mRNA increased at day 3-5 and declined at day 8-10. Serum levels of TGFbeta1 demonstrated a comparable course. The present data suggest that corticosteroids induce the expression of TGFbeta1 in vivo. This is might be an other mechanism by which corticosteroids mediate immunosuppression.

Herpes zoster guideline of the German Dermatology Society (DDG).

Varicella zoster virus (VZV) causes varicella (chickenpox), remains dormant in dorsal root and cranial nerve ganglia and can be reactivated as a consequence of declining VZV-specific cellular immunity leading to herpes zoster (shingles). Patients older than 50 years of age affected by herpes zoster may suffer a significant decrease of quality of life. These patients and immunocompromised individuals are at increased risks for severe complications, involving the eye, the peripheral and the central nervous system (prolonged pain, postherpetic neuralgia). Such complications occur with and without cutaneous symptoms. The German Dermatology Society (DDG) has released guidelines in order to guarantee updated management to anyone affected by herpes zoster. Diagnosis is primarily clinical. The gold standard of laboratory diagnosis comprises PCR and direct identification of VZV in cell cultures. Detection of IgM- and IgA-anti VZV antibodies may be helpful in immunocompromised patients. Therapy has become very effective in the last years. Systemic antiviral therapy is able to shorten the healing process of acute herpes zoster, to prevent or to alleviate pain and other acute and chronic complications, particularly, when given within 48 h to a maximum of 72 h after onset of the rash. Systemic antiviral therapy is urgently indicated in patients beyond the age of 50 years and in patients at any age with herpes zoster in the head and neck area, especially in patients with zoster ophthalmicus. Further urgent indications are severe herpes zoster on the trunk and on the extremities, herpes zoster in immunosuppressed patients and in patients with severe atopic dermatitis and severe ekzema. Only relative indications for antiviral therapy exist in patients younger than 50 years with zoster on the trunk and on the extremities. In Germany acyclovir, valacyclovir, famciclovir and brivudin are approved for the systemic antiviral treatment of herpes zoster. These compounds are all well tolerated by the patients and do not differ with regard to efficacy and safety. Brivudin has a markedly higher anti-VZV potency than oral acyclovir, valacyclovir and famciclovir and thus offers a simpler dosing regimen. It must be given only once daily during 7 days in comparison to three and five times dosing per day of valacyclovir, famciclovir and acyclovir, respectively. Brivudin is an antiviral agent with no nephrotoxic properties, which is an advantage when compared to acyclovir. The most important aim of therapy of herpes zoster is to achieve painlessness. Appropriately dosed analgesics in combination with a neuroactive agent (i.e. amitriptylin) are very helpful when given together with antiviral therapy. The additive therapy with corticosteroids may shorten the degree and duration of acute zoster pain, but has no essential effect on the development of postherpetic neuralgia, which is a very difficult condition to treat. Thus early presentation to a pain therapist is recommended in specific cases.

Visual evoked blink reflex in optic neuritis.

The optically evoked blink reflex (BR) was recorded in 30 patients (20 females, 10 males) with primary acute optic neuritis (ON) unassociated with other CNS disorders. The reflex was studied in the acute stage between the 1st and 6th day after onset, during the 1st month following the acute stage once a week, and then 2 and 6 months later. In patients in whom a relapse occurred, the programme was restarted from the beginning. Control values were taken from prior investigations in 50 healthy subjects. In the acute stage differences in the amplitudes were present in 26 patients, but the latencies remained within normal limits. Six patients (20%) developed multiple sclerosis during the 5-year follow-up until December 1985. In these cases the optic BR showed increased latencies and decreased amplitudes. In patients without manifestation of multiple sclerosis the BR remained normal. In 7 patients cranial magnetic resonance imaging (MRI) was done. All patients with some abnormalities in the visual BR also had an abnormal MRI. The pattern-shift visual evoked potentials were abnormal in the acute stage of ON in 90%, and CSF abnormalities were found in 56.6%. In 4 patients (13%) the visual BR could not be evoked at all.

Trigeminal and facial nerve involvement in Charcot-Marie-Tooth disease. An electrodiagnostic study.

The electrically and optically elicited orbicularis oculi reflex (OOR) and facial nerve latency were investigated in eight patients from three families. Each had autosomal dominant peroneal muscular atrophy. In a family with the dominantly inherited hypertrophic type markedly delayed latencies of the early reflex component of the OOR were found while the facial nerve had remained unaffected. These findings were interpreted as an indicator for supraorbital nerve involvement. In the other two investigated families of hypertrophic and neuronal type, a prolonged facial nerve latency was demonstrable. In these cases the latency of the optically evoked blink reflex was also delayed, while the latency of the early reflex component of the OOR was within normal limits or only slightly delayed. It is assumed that the different degree of cranial nerve involvement in these families is the expression of their genetically determined peculiarities.

Familial meralgia paresthetica with an autosomal dominant trait.

Familial occurrence of Meralgia paresthetica is uncommon. Only few familial case studies have been reported up to now. The author presents a family with Meralgia in four generations, suggesting a distinctly autosomal dominant trait.

Bilateral traumatic extracranial aneurysms of the internal carotid artery with delayed brain infarction.

A 24-year-old woman with a left-sided cerebral infarction presented with hemiplegia and aphasia. Five months earlier she had had a closed head injury. Angiography revealed bilateral extracranial post-traumatic aneurysms of the internal carotid artery at the atlanto-axial level. There was full recovery without operative treatment within a week.

Unusual EEG findings in a case of Creutzfeldt-Jakob disease.

A case is reported of histopathologically verified Creutzfeldt-Jakob disease of long duration (more than 3 years) with some clinical peculiarities. The prominent peculiarity was a nearly normal EEG during repeated examinations, even in the terminal stage.

Potential role of transforming growth factor-beta 1 in terminating the immune response in patients with Guillain-Barré syndrome.

T-cell activation and proinflammatory cytokines seem to be important in promoting the disease activity in Guillain-Barré syndrome (GBS). Transforming growth factor-beta 1 (TGF-beta 1) is a multifunctional peptide with potent immunosuppressive activity, and can therefore be considered a putative disease-limiting cytokine. We determined levels of soluble TGF-beta 1 in the serum of 12 patients with GBS in serial investigations during the course of the disease, in 12 patients with other noninflammatory neurological diseases (OND), and in 12 healthy control subjects. Levels of biologically active and total TGF-beta 1 were significantly increased in patients with GBS compared with patients with OND and healthy controls. During the course of GBS, levels of TGF-beta 1 peaked in the plateau phase before onset of recovery. During the recovery phase levels of TGF-beta 1 decreased but still exceeded significantly the levels in patients with OND and healthy controls. The differences were more marked with biologically active than with total TGF-beta 1. The temporal relationship between increased serum levels of TGF-beta 1 and the end of the progressive phase indicates that TGF-beta 1 has a role in terminating the pathological immune response in GBS. These findings suggest that TGF-beta 1 may be important in recovery from GBS.

Cerebrospinal fluid cytology in granulocytic sarcoma with meningeal extension but without bone marrow involvement.

Granulocytic sarcoma (GS) is a localized tumour of immature granulocytes that is usually associated with myelogenous leukaemia. We report an unusual case of mastoid GS with meningeal extension but no bone marrow involvement on presentation. Histological examination of the surgical specimen and the characteristic cerebrospinal fluid (CSF) cytology showing cytoplasmic granulations and Auer bodies led to the diagnosis of GS. Positive cytochemical staining of the immature CSF cells for naphthol-ASD chloroacetate esterase and myeloperoxidase confirmed their myeloid origin. Immunophenotyping did not reveal common acute lymphoblastic leukaemia antigen, cytokeratin, T- or B-cell antigens. The patient underwent surgical resection of the localized tumour, followed by radiation therapy, intrathecal and systemic chemotherapy, as if he had acute myelogenous leukaemia (AML). He did not develop AML in the 21 months after the tumour resection. This case emphasizes the value of CSF cytological examination of tumour cells and the use of an immunocytochemical marker for differentiating GS from malignant lymphoma.

The soluble 60-kDa tumour necrosis factor receptor: no difference found between patients with relapsing-remitting multiple sclerosis and controls: increasing levels are associated with the recovery from Guillain-Barré syndrome.

We determined serum and cerebrospinal fluid (CSF) levels of the soluble 60-kDa tumour necrosis factor (TNF) receptor (sTNF-R p60) in 50 patients with relapsing-remitting multiple sclerosis (MS) and in 18 patients with Guillain-Barré syndrome (GBS). Neither in serum nor in CSF samples was there a statistically significant difference between mean receptor concentrations of patients with MS (serum: 1064, SD 262 pg/ml; CSF: 555, SD 130 pg/ml), with other noninflammatory neurological diseases (serum: 1008, SD 248 pg/ml; CSF: 530, SD 112 pg/ml) and with healthy control subjects (serum: 918, SD 180 pg/ml). In order to determine disease activity, magnetic resonance imaging (MRI) of the brain was performed in all MS patients. The mean sTNF-R p60 levels of patients who showed gadolinium DTPA enhancement on MRI were not different from those without enhancement (1034, SD 274 pg/ml vs 1099, SD 248 pg/ml in serum samples and 546, SD 109 pg/ml vs 565, SD 152 pg/ml in CSF samples). In GBS, the sTNF-R p60 levels of serum and CSF samples were significantly higher than in MS and all control groups except for the group with viral meningitis (VM) (GBS: 1544, SD 834 pg/ml in serum, 882, SD 147 pg/ml in CSF; VM: 1518, SD 375 pg/ml in serum, 1131, SD 611 pg/ml in CSF; P < 0.001 for serum samples and P < 0.005 for CSF samples). Serial serum sTNF-R p60 measurements in 13 patients with GBS showed an increase in receptor levels parallel with the recovery from the disease (1276, SD 374 pg/ml at the time of disease onset, 1554, SD 482 pg/ml 14-24 days later and 1787, SD 525 pg/ml after 28-32 days). From our results and the conflicting data of previous studies, we could not agree with the suggestion that the assessment of sTNF-R p60 in MS patients is a useful marker for disease activity. In GBS, subsequently increasing sTNF-R p60 levels are associated with recovery from the disease. It remains to be shown whether they might represent a relevant pathogenetic factor during this stage of GBS.

T4, T3 and rT3 levels in serum and cerebrospinal fluid of patients with amyotrophic lateral sclerosis.

Thyronine (T4), triiodothyronine (T3), and reverse-triiodothyronine (rT3) levels were evaluated in cerebrospinal fluid (CSF) and in serum of 12 patients with definite amyotrophic lateral sclerosis (ALS) by specific radioimmunoassays. Circulating microsomal and thyroglobulin antibodies were also evaluated. In all patients serum levels of T4, T3 and rT3 were within normal limits. In CSF, the rT3 levels were significantly elevated to 0.118 micrograms/l (mean), the T4 levels were not significantly elevated, and the T3 levels were below the detection limit of 0.03 micrograms/l. A correlation between the elevated rT3 levels in CSF and the severity or type of ALS could not be demonstrated by this study. The antithyroid antibodies (thyroglobulin antibodies, microsomal antibodies) showed normal titres and did not suggest disturbances of thyroid autoimmunity in the patients with ALS.

Detection of transforming growth factor beta 1 mRNA in cerebrospinal fluid cells of patients with meningitis by non-radioactive in situ hybridization.

Meningitis is a serious disease mostly caused by viral or bacterial infections. In complicated cases it may lead to brain damage and death. The infection and cell damage result in a cellular and immunological response. Following this, a high secretion of cytokines can be expected. Cytokines, especially tumour necrosis factor alpha (TNF-alpha) and interleukin-1 (IL-1), promote the inflammatory reactions in the subarachnoid space. Transforming growth factor beta 1 (TGF-beta 1) has antagonistic effects on TNF-alpha and IL-1-mediated processes. Therefore, it suppresses inflammatory reactions. To observe the expression of TGF-beta 1 in transcellular signalling in the inflammatory processes of meningitis, we investigated TGF-beta 1 mRNA in cells in the cerebrospinal fluid of three patients with meningitis by non-radioactive in situ hybridization. All patients fulfilled the usual clinical criteria of meningitis. In one case Neisseria menigitidis could be identified as the pathogenic agent. In the remainder, no agent could be isolated. In all cytological preparations of the cerebrospinal fluid of these patients a high level of TGF-beta 1 mRNA was detectable in the cell populations. It was possible to distinguish between the different cell types of the cerebrospinal fluid and to attach the mRNA expression to them. On the one hand, this makes it possible to investigate pathogenesis and defence mechanisms in bacterial and aseptic meningitis on a cellular level; on the other hand, it may open new perspectives in the control of disease development, prognosis, diagnosis and supporting therapy.

Polyneuropathy associated with chronic hypoxaemia: prevalence in patients with chronic obstructive pulmonary disease.

The prevalence of clinical and electrophysiological signs of peripheral nerve disease was evaluated in 151 patients with chronic obstructive pulmonary disease. Patients with concomitant disorders affecting the peripheral nervous system were excluded. Thirty patients had clinical signs of a mild sensorimotor and distal neuropathy and 13 additional patients had only electrophysiological abnormalities. The rate and the severity of the neuropathy correlated with the severity of chronic hypoxaemia. Three out of 20 patients with mild hypoxaemia (PaO2 less than 15 mm Hg below normal) had polyneuropathy as compared with 15 out of 36 with severe hypoxaemia (PaO2 more than 30 mm Hg below normal (rates different at the 10% level)). PaO2 and age were the only variables discriminating between patients with and without peripheral neuropathy.