P. Diószeghy

Cerebral blood flow and glucose metabolism in mitochondrial disorders.

Objective: To investigate cerebral metabolism by 2-[18F]fluorodeoxy-d-glucose (FDG) uptake using PET and cerebrovascular reverse capacity by transcranial Doppler sonography (TCD) in different mitochondrial diseases (mitochondrial myopathy; mitochondrial encephalopathy, lactacidosis, and stroke-like episodes [MELAS]; and chronic external ophthalmoplegia). Background: Previous studies on individual patients with mitochondriopathies revealed abnormal accumulations of mitochondria in endothelium, smooth muscle cells, and pericytes of blood vessels in different parts of the nervous system (cerebrum, cerebellum, sural nerve) and skeletal muscle. On this basis, some investigators suggested a pathogenic role of vascular involvement in the MELAS syndrome and other encephalopathies. {smhd1} Design/Methods: The authors investigated neuronal metabolism and cerebrovascular involvement with PET in 5 cases and with TCD with acetazolamide stimulation in 15 cases. The patients were divided into three groups: 1) interictal MELAS (n = 4); 2) progressive external ophthalmoplegia (n = 6); and 3) pure mitochondrial myopathy and neuropathy (n = 5). The results were compared with those from matched normal control subjects. The diagnoses were based on clinical phenotype as well as histopathologic and molecular analysis. Results: Cerebral glucose uptake was impaired in all patients, both with and without CNS symptoms, particularly in the occipital and temporal lobes. The vasoreactivity of the small arterioles to acetazolamide did not differ significantly between the patients and healthy control subjects or between the different groups of mitochondrial disorders. Conclusions: MELAS does not appear to be a functional disturbance of arterioles leading to an ischemic vascular event. The clinical symptoms in MELAS are not the result of a mitochondrial angiopathy but are the consequences of a mitochondrial cytopathy affecting neurons or glia. There is no correlation between the decreased glucose metabolism and the duration of the disease.

No correlation between impairment of cerebrovascular reserve capacity and electrophysiologically assessed severity of neuropathy in noninsulin-dependent diabetes mellitus.

INTRODUCTION Microvascular abnormalities have an important role in the most frequent neurological complications of diabetes mellitus: neuropathy and cerebrovascular disorders. Severity of neuropathy as well as of cerebral microvascular damage can be quantitatively evaluated by instrumental methods like nerve conduction studies and transcranial Doppler. In the present study, we investigated whether a correlation exists between the severity of peripheral neuropathy and the impairment of cerebrovascular reserve capacity (CRC) in 20 patients with Type 2 diabetes mellitus. METHODS CRC was measured by transcranial Doppler and defined as the maximal percentage increase in blood flow velocity in the middle cerebral artery within 20 min after an intravenous dose of 1000 mg of acetazolamide. Nerve conduction studies of the median, ulnar, peroneal, and sural nerves were performed. Severity of neuropathy was scored based on conduction velocities, amplitudes, and distal latencies. RESULTS There was no correlation between the neuropathic score and CRC (R= .003, P= .99). Neither CRC nor the neuropathic score correlated significantly with age, duration of diabetes, and serum values of HbA(1c), glucose, insulin, von Willebrand factor, and alpha(2) - macroglobulin. Severity of neuropathy but not CRC correlated with microalbuminuria (R= .47, P= .038 and R= .14, P= .54). Improper treatment reflected by HbA(1c) >10% was associated with significantly more severe albuminuria, higher actual blood glucose level, higher von Willebrand factor activity, and marginally higher neuropathic score (21 vs. 13, P=.096), but was not associated with CRC (44% vs. 42%, P= .81). When duration of diabetes was dichotomized to 15 years and less or over 15 years, CRC was significantly smaller (35% vs. 50%, P= .036) and neuropathy was more severe in the subgroup with longer diabetes duration (19 vs. 11.5 points, P= .07). CONCLUSIONS Although both CRC and peripheral nerve function are affected more severely in patients with long-lasting Type 2 diabetes mellitus, damage in the cerebrovascular system and in the long peripheral nerves occur independently. As in diabetes mellitus pathological changes in autonomic and large peripheral nerves develop simultaneously, decreased CRC in diabetic patients might be predominantly due to structural changes of resistance arteries or to metabolic than to neurogenic factors.

Central core and nemaline rods in the same patient.

Abstract It is quite rare, that central cores and nemaline bodies occur in the same individual. We describe the case of a 12-year-old girl, who was born with bilateral congenital hip dislocation. Her early motor milestones were delayed. Due to proximal weakness of the lower extremities she has never been able to walk. The family history was negative. Muscle histology, histochemistry and electron microscopic studies showed a central core in nearly all muscle fibers, and nemaline rods in a few. The earlier literature and new genetical findings concerning these mucle abnormalities are also briefly summarized.

Otoacoustic emission in myasthenia gravis patients and the role of efferent activation

We performed transient evoked otoacoustic emission (TEOAE) measurements on 29 ears of myasthenia gravis (MG) patients. The purpose of the study was to support the role of acetylcholine (ACh) in the efferent innervation of cochlear outer hair cells (OHCs). Another aim was to establish additional diagnostic tools for the early determination of MG. Initially, threshold audiometry and impedance measurements showed normal values on the ears examined. The main finding was that TEOAE values were significantly lower in MG patients than in healthy controls. Mestinon, a reversible cholinesterase inhibitor, resulted in a significant increase in mean values of TEOAEs, although these values were still lower than normal. The results suggest that in MG, acetylcholine receptor (AChR) autoantibodies inhibit the function of OHC AChRs. Thus, the TEOAE generated by the active movements of OHCs is decreased in MG. Mestinon prevents the degradation of ACh, and thus stimulates efferent function and increases TEOAE values. The results obtained in this study support the role of ACh in the efferent function of OHC, as well as the impaired function of hair cell AChRs in MG patients. Consequently, measuring TEOAEs may be useful in the early diagnosis of some forms of MG. These results reinforce the importance of collaboration between neurologists and otolaryngologists in the management of diseases with pathological neurotransmission.

Inflammatory Changes in Facioscapulohumeral Muscular Dystrophy

SummaryFifteen patients (10 familial and 5 sporadic cases) with facioscapulohumeral dystrophy were studied with regard to the presence of inflammatory changes. Mononuclear infiltrations were not characteristic of any stage of the disease, but they may be present in differring degrees during the whole course of the process. However, their lack or presence was uniform in the affected families, suggesting that the appearance of infiltrations may be genetically determined. Parallel with the presence of cell infiltrations, the serum creatine kinase (CK) activity was moderately increased and the progress of the disease was slightly accelerated. The relation of these phenomena to polymyositis and the diagnostic difficulties are discussed.

The significance of simultaneous estimation of serum creatine kinase and myoglobin in neuromuscular diseases

SummarySerum creatine kinase (CK) and myoglobin (Mb) levels were measured in patients with different neuromuscular diseases, carriers of X-linked Duchenne-type muscular dystrophy and normal volunteers. The highest levels were found in Duchenne dystrophy and both values decreased in parallel with age. In patients suffering from limb-girdle dystrophy the increases in CK activity and Mb concentration were also pronounced. However, there were families with normal and others with elevated CK and Mb levels in facioscapulohumeral dystrophy. In neurogenic atrophies both CK and Mb levels generally increased only slightly. Serum Mb and CK levels have similar values as indicators of muscle damage in primary and secondary skeletal muscle disorders. The serum Mb level helps in the detection of carriers but is not more sensitive than CK measurement.

Ion Concentrations in Serum and Cerebrospinal Fluid of Patients with Neuromuscular Diseases

SummaryThe Na+, K+, Ca2+, Mg2+, Cl−, and Pi concentrations in serum and lumbar CSF of 17 controls and 62 patients with neuromuscular diseases were determined and the values statistically evaluated. Although alterations in ion concentrations specifical to different groups were not observed in either of these biological fluids, the significant increase in serum Pi concentration in Duchenne muscular dystrophy seems to be remarkable. It is suggested that the possible alterations in the ion content of the serum and CSF may contribute additional data to the diagnosis of various neuromuscular diseases.ZusammenfassungBei 62 Patienten mit neuromuskulären Erkrankungen und bei 17 Kontrollpatienten wurde die Konzentration von Na+, K+, Ca2+, Mg2+, Cl− und anorganischem Phosphor (Pi) im Serum und im lumbalen Liquor vergleichend gemessen, und die Werte wurden statistisch bearbeitet. Obwohl keine für die verschiedenen Erkrankungstypen charakteristischen Veränderungen beobachtet werden konnten, ist die signifikante Erhöhung der Pi-Konzentration im Serum bei Duchenne-Dystrophie doch erwähnenswert. Die eventuellen Veränderungen der Ionenkonzentration im Serum und im Liquor können zur Diagnosestellung bei verschiedenen neuromuskulären Erkrankungen beitragen.

Lipid peroxidation and superoxide dismutase activity in muscle and erythrocytes in adult muscular dystrophies and neurogenic atrophies

SummaryLipid peroxidation (LP) and superoxide dismutase (SOD) activity were determined in erythrocytes and skeletal muscle obtained from patients with limb-girdle and facioscapulohumeral muscular dystrophies, neurogenic atrophies and from age-matched control subjects. Neither lipid peroxidation nor SOD activity in erythrocytes of patients differed from control values. SOD activity and LP in muscle specimens were also normal in types of neurogenic atrophy. Lipid peroxidation in the muscle from patients with adult types of muscular dystrophy had a tendency to be increased. The values were widely scattered, the highest being obtained in the older patients with long duration of disease.

Peripheral nerves are progressively involved in multiple sclerosis – A hypothesis from a pilot study of temperature sensitized electroneurographic screening

Multiple sclerosis (MS) is primarily a disease of the central nervous system. Although the involvement of the peripheral nervous system in MS was suggested over 100 years ago, the issue is still controversial, and it is generally accepted that except for the optic nerve the peripheral nerves are left unaffected by the disease. We hypothesize, that an electroneurographical study if thorough enough, may reveal differences in some nerve conduction parameters between MS patients and healthy subjects. Second, we assume that the sensitivity of nerve conduction measurements might be increased if performed at a range of temperatures, reflecting a differential effect of cooling and warming on the peripheral nerve conduction parameters in MS patients and controls. Finally, we expect that the differences in these parameters between controls and MS patients will increase with the progression of the disease. To test these hypotheses in a pilot study, we performed a detailed analysis of the motor and sensory nerve conduction features of the right median nerve in 13 MS patients and 13 controls at 5 degrees C increments between 20 and 40 degrees C, and repeated these measurements after 3 years. The motor latencies were 0.3-0.6 ms longer in MS patients compared to the controls both initially and 3 years later (0.058<p<0.09). The durations and areas of the compound motor action potential (CMAP) appeared more sensitive to changes in temperature in the MS group (0.057<p<0.1). The change in both distal motor latency and sensory latency per unit change in temperature decreased significantly in 3 years within the MS but not in the control group. These results suggest a mild and progressive involvement of the PNS in MS. Most differences in this pilot study were on the border of statistical significance therefore our hypotheses should be confirmed in studies with larger sample size.

Three novel mutations and genetic epidemiology analysis of the Gap Junction Beta 1 (GJB1) gene among Hungarian Charcot-Marie-Tooth disease patients.

Pathogenic variants of the gap junction beta 1 (GJB1) gene are responsible for the Charcot-Marie-Tooth neuropathy X type 1 (CMTX1). In this study, we report the mutation frequency of GJB1 in 210 Hungarian CMT patients and the phenotype comparison between male and female CMTX1 patients. Altogether, 13 missense substitutions were found in the GJB1 gene. Among them, 10 have been previously described as pathogenic variants (p.Arg15Trp, p.Val63Ile, p.Leu89Val, p.Ala96Gly, p.Arg107Trp, p.Arg142Gln, p.Arg164Trp, p.Arg164Gln, p.Pro172Ala and p.Asn205Ser), while 3 were novel, likely pathogenic alterations (p.Val13Glu, p.Glu186Gly, p.Met194Ile). These variants were not present in controls and were predicted as disease causing by in silico analysis. The frequency of the variants was 6.7% in our cohort which refers to a common cause of hereditary neuropathy among Hungarian patients. In addition to the classical phenotype, CNS involvement was proved in 26.1% of the CMTX1 patients. GJB1 pathogenic alterations were found mainly in males but we also detected them in female probands. The statistical analysis of CMTX1 patients revealed a significant difference between the two genders regarding the age of onset, Charcot-Marie-Tooth neuropathy and examination scores.