Polymorphism in the TOMM40 gene modifies the risk of developing sporadic inclusion body myositis and the age of onset of symptoms.

A polyT repeat in an intronic polymorphism (rs10524523) in the TOMM40 gene, which encodes an outer mitochondrial membrane translocase involved in the transport of amyloid-ß and other proteins into mitochondria, has been implicated in Alzheimer's disease and APOE-TOMM40 genotypes have been shown to modify disease risk and age at onset of symptoms. Because of the similarities between Alzheimer's disease and sporadic inclusion body myositis (s-IBM), and the importance of amyloid-ß and mitochondrial changes in s-IBM, we investigated whether variation in poly-T repeat lengths in rs10524523 also influence susceptibility and age at onset in a cohort of 90 Caucasian s-IBM patients (55 males; age 69.1 ± 9.6). In carriers of APOE ε3/ε3 or ε3/ε4, genotypes with a very long (VL) poly-T repeat were under-represented in s-IBM compared to controls and were associated with a later age at symptom onset, suggesting that these genotypes may be protective. Our study is the first to suggest that polymorphisms in genes controlling mitochondrial function can influence susceptibility to s-IBM and have disease modifying effects. However, further studies in other s-IBM populations are needed to confirm these findings, as well as expression studies of different TOMM40 alleles in muscle tissue.

Neurology of Fabry disease.

BACKGROUND: Fabry disease has diverse neurological manifestations, many of which influence morbidity and quality of life. AIMS: The aim of the study was to document the clinical and subclinical neurological manifestations in a cohort of Australian patients with Fabry disease, using multiple clinical tools and a multidisciplinary approach. METHODS: Participants completed focused questionnaires and underwent clinical neurological examination, Neurocognitive testing using Mini Mental State Examination and Neuropsychiatry Unit Cognitive Screen, Quantitative Sensory Testing (QST), autonomic assessment using RR interval variation, intracranial magnetic resonance imaging (MRI) and audiology. In subsets of patients who had previously undergone QST and/or prospective serial quality-of-life assessments over the previous 5 years, results before and after enzyme replacement therapy were compared. RESULTS: Twenty hemizygotes and two heterozygotes were recruited. The age (mean +/- standard deviation (SD)) of male participants was 40.4 +/- 11.9 years (range 20-62 years); the women were aged between 20 and 56 years. Increasing age was strongly associated with increasing neurological disability. Clinical peripheral neuropathy predominantly affected thermal sensation in all patients, with variable involvement of pinprick and light touch. QST confirmed these findings. Clinical cerebellar tests were commonly abnormal: this has not been previously reported in the absence of symptomatic cerebrovascular disease. There was hearing loss was in 90% of patients and no patient older than 44 years had normal hearing. MRI lesion prevalence increased with age. Despite neurological complications being common, formal cognitive testing was basically normal. QST thresholds for pain showed a significant change after enzyme replacement therapy. CONCLUSIONS: Neurological complications in Fabry disease are common, complex and may be devastating. All patients studied had neurological involvement, with protean and diverse manifestations.

Clinical features of Fabry's disease in Australian patients.

BACKGROUND: Anticipating the prospect of specific treatment, we studied a large group of Australians with Fabry's disease. AIMS: We aimed to: (i) document the clinical features of Fabry's disease in Australian patients, (ii) test the hypothesis that clinical features vary with specific mutation and blood group and (iii) assess small-fibre peripheral nerve function. METHODS: A questionnaire was forwarded to all Australian patients known to us. Patients were invited to attend for clinical, renal cardiac, ophthalmological and neurological assessment. RESULTS: Sixty-seven patients (29 men and 38 women) from 18 families participated. Diagnosis in index cases was delayed by > or = 10 years in nearly all families. Common clinical features are: (i) episodic acroparaesthesia (100% of hemizygotes; 53% of heterozygotes), (ii) anhydrosis (93%; 1%), (iii) characteristic rash (93%; 13%), (iv) renal disease (69%; 21%), (v) ischaemic heart disease (28%; 26%), (vi) palpitations (62%; 29%), (vii) mitral valve murmurs (37%; 23%) and (viii) premature cerebrovascular disease (31%; 5%). Ophthalmic findings of cornea verticillata (96%; 76%) and anterior cataract (48%; 14%) were common. Findings were variable within and between families. In women, anhydrosis reliably predicts the presence of significant Fabry's renal disease. Small nerve fibre testing using quantitative sensory testing was clearly abnormal in 95% of male patients, and in those female patients with paraesthesiae. CONCLUSIONS: Symptoms of anhydrosis, acroparaesthesiae, rash and renal disease suggest diagnosis of Fabry's. Women are commonly symptomatic, and the advent of therapy highlights the practical advantage of earlier diagnosis.

Mitochondrial DNA variants in inclusion body myositis.

Mitochondrial DNA variants have been shown to be associated with many diseases. Mutations at mitochondrial DNA nucleotide positions 3192, 3196, 3397 and 4336 have been described in association with late-onset Alzheimer's disease. The pathological similarities between inclusion body myositis and Alzheimer's disease prompted an analysis of the relationship between the reported mutations and sporadic inclusion body myositis. The 4336G variant was not significantly increased in patients with inclusion body myositis or Alzheimer's disease when compared to controls. None of the patients with inclusion body myositis carried mutations at nucleotide positions 3192, 3196 and 3397. A transition at nucleotide position 4580 was detected in some patients with inclusion body myositis and Alzheimer's disease but was not significantly higher in frequency when compared to controls. Phylogenetic analysis showed that the 4336G and 4580A variants clustered together in their respective group. A group of patients with inclusion body myositis also clustered together on a separate branch of the phylogenetic tree. Closer investigation of this group revealed a common polymorphism at nucleotide position 16311. The frequency of the 16311C variant was higher in inclusion body myositis than in Alzheimer's disease and controls, although when only caucasian patients were considered the increased frequency was not statistically significant. Further studies will be required to determine whether this variant plays a role in the pathogenesis of inclusion body myositis.

Mapping of a candidate region for susceptibility to inclusion body myositis in the human major histocompatibility complex.

Inclusion body myositis (IBM) is a form of idiopathic inflammatory myopathy of unknown aetiology. A strong association with HLA class II (HLA-DR3) suggested a role for genes in the human major histocompatibility complex (MHC) in the predisposition to this disease. In this study, we have taken advantage of the ancestral haplotype (AH) concept and historical recombinations to map for a possible susceptibility gene(s) in the MHC. We performed detailed typing of three MHC-related HSP70 genes and defined allelic combinations in the context of MHC AH. We also modified existing methods to give a simple and accurate method for typing two TNF microsatellites. Using the HSP70 and TNF markers and HLA-DR, -B, and C4 typing of our patients with IBM, we defined a potential site for the MHC-associated susceptibility gene(s) in the region between HLA-DR and C4.

Magnetic resonance imaging in subacute combined degeneration of the spinal cord.

We describe the magnetic resonance imaging (MRI) abnormalities in a patient with subacute combined degeneration of the spinal cord (vitamin B12-deficient myelopathy). T2-weighted images revealed symmetric, high signal abnormalities in the posterior columns of the cervical cord, which resolved following recovery from the disease. Recognition of this MRI pattern is important because this is likely to represent an early, potentially reversible stage of the disease.

Natural killer cell lymphoproliferative disease associated with combined peripheral and autonomic neuropathy.

Natural killer cell proliferation is an uncommon haematological disorder that has a number of different clinical manifestations. There have been only two prior reports linking this process with neurological disease, both reports describing peripheral neuropathy. We report the case of a young man presenting with a short history of lethargy, lower limb paraesthesia and marked weight loss who was found to have a natural killer cell lymphocytosis and features of both an autonomic and a peripheral neuropathy. The patient's clinical features responsed to a combination of cytotoxic and immunosuppressive therapy, and the patient is now clinically stable with mild ongoing lymphocytosis, diarrhoea and postural hypotension. We review the possible pathological link between natural killer cells and neurological disease.

Association of acute inflammatory demyelinating polyneuropathy with acute lymphoblastic leukaemia and HLA-A11.

Acute inflammatory demyelinating polyneuropathy (Guillain-Barré syndrome) developed in three patients receiving chemotherapy for acute lymphoblastic leukaemia or the closely related entity lymphoblastic lymphoma, a relationship that has not been previously described. The HLA-A11 antigen was expressed by all patients, two of whom were Chinese, raising the possibility of a genetically-based immunological predisposition to GBS in this patient group.

Risk factors for developing multiple sclerosis after childhood optic neuritis.

We reviewed the records of all children (younger than 16 years of age) who presented with a diagnosis of optic neuritis (ON) identified through the comprehensive records-linkage system at the Mayo Clinic and identified 94 cases between 1950 and 1988 with a documented history of idiopathic ON. Detailed follow-up information was available on 79 patients, with a median length of follow-up of 19.4 years. Life-table analysis showed that 13% of the 79 patients with isolated ON had progressed to clinically or laboratory-supported definite multiple sclerosis (MS) by 10 years of follow-up, 19% by 20 years, 22% by 30 years, and 26% by 40 years. Gender, age, funduscopic findings, visual acuity, or family history of either ON or MS did not predict the development of MS. The presence of bilateral sequential or recurrent ON increased the risk of developing MS (p = 0.002; hazard ratio = 5.09), whereas the presence of infection within 2 weeks before the onset of ON decreased the risk of developing MS (p = 0.060; hazard ratio = 0.24). This study of childhood ON supports the lower risk of recurrence and progression to MS compared with adults.

Facilitatory effect of thinking about movement on magnetic motor-evoked potentials.

To investigate the facilitatory effect of thinking about movement on motor evoked potential (MEP) amplitude, we recorded MEPs in two test muscles during rest, with the subject thinking about contracting the test muscle but without subsequent contraction, and during 10% maximum voluntary contraction. Stimuli were delivered at 10% above resting motor threshold and at 90-100% stimulator output. H-reflexes, recorded in flexor carpi radialis, were obtained during rest and think conditions. MEP threshold was lower during the think condition (P = 0.004). At both stimulus intensities, median MEP amplitudes and areas were significantly (P < 0.001) larger during the think paradigm compared with rest. This effect was greater at the lower stimulus intensity. There was no significant difference in latency (P = 0.15). In 4/8 subjects, H-reflex amplitudes were mildly facilitated (P < 0.05) during the think condition. We conclude that thinking about movement without detectable EMG activity has a facilitatory effect on magnetic MEPs. The absence of a MEP latency shift between rest and think conditions and absence of a consistent increase in H-reflex amplitude suggests this effect occurs largely at the cortical level. In some subjects, however, an increase in spinal motoneuron excitability may also contribute.

Magnetic stimulation of the motor cortex: Clinical applications.

Transcranial magnetic cortical stimulation provides the clinical neurophysiologist with a method to examine alterations in the function of central motor pathways in diseases affecting the motor system. The technique has great research potential and has led to increased understanding of intracortical physiology, corticospinal tract function, motor system plasticity and motor control. Subclinical cerebral and spinal cord lesions may be demonstrated, and the technique has a potential role for quantification and monitoring of disease progression, and for early prognostication after stroke. Intraoperative monitoring of motor evoked potentials (MEP) is of value during spinal cord surgery, but due to attenuation of magnetic MEPs during anaesthesia, transcranial electrical stimulation is more appropriate for intraoperative recordings.

Modulation of motor activity by cutaneous input: inhibition of the magnetic motor evoked potential by digital electrical stimulation.

We examined the inhibitory effect of a brief train of digital (D2) electrical stimuli at 4 times perception threshold on transcranial magnetic motor evoked potentials (MEPs) recorded from abductor pollicis brevis (APB) and flexor carpi radialis (FCR) muscles ipsilateral to the side of D2 stimulation. We compared this to the inhibitory effect of ipsilateral D2 stimulation on averaged rectified EMG recorded at 10% maximum voluntary contraction and on F-responses and H-reflexes recorded from these same muscles. We also compared MEPs recorded following D2 stimulation just above perception threshold to MEPs following higher intensity D2 stimulation. As well, we assessed the effect of preceding D2 stimulation on MEPs recorded from a relaxed versus tonically contracted hand muscle. D2 stimulation elicited a triphasic response of modest MEP facilitation followed by inhibition and further facilitation. The duration and onset of MEP inhibition correlated with those of the initial period of rectified EMG inhibition, however, the magnitude of MEP inhibition was generally less than the magnitude of EMG inhibition, consistent with a greater inhibitory effect of digital afferents on smaller motor neurons. MEPs were not facilitated during the rebound of EMG activity (the E2 period) that usually followed the initial period of EMG inhibition (I1 period). The behavior of H-reflexes and F-responses following ipsilateral D2 stimulation suggested that inhibition of both EMG and MEPs is not mediated via presynaptic inhibition of Ia afferents, and that inhibition is augmented by descending rather than segmental input to spinal motor neurons. Tonic contraction of the target muscle during D2 stimulation decreased the inhibitory effect of the preceding digital stimulus possibly due to recruitment of larger spinal motor neurons less likely to be inhibited by cutaneous input.

Assessment of cortical motor output: compound muscle action potential versus twitch force recording.

To determine whether motor evoked potential (MEP) amplitude and area are accurate measurements of the magnitude of response to magnetic cortical stimulation, we simultaneously recorded the twitch and MEP in the first dorsal interosseous muscle of 8 normal subjects. Consecutive stimuli were delivered at increasing stimulus intensities (SI) or with increasing levels of background voluntary muscle contraction (BVC). There was stimulus to stimulus variability in MEP amplitude, area and twitch force. At low SI and at low levels of background contraction, there was a good correlation between twitch amplitude and MEP amplitude and area (r = 0.6-0.96, P < 0.005). Increasing either variable caused the correlation to decrease significantly (r = 0.02-0.31, P > 0.01). With increasing SI, MEP amplitude and area plateaued but twitch force continued to increase. A similar pattern was observed with higher levels of background muscle contraction although in some subjects a second increase in MEP amplitude and area was seen. Collision experiments demonstrated that the amplitude of the EMG activity resulting from repetitive motoneuron firing increased as SI was increased. This is due to multiple descending volleys which result in repetitive firing of some spinal motoneurons. Rapid, repetitive firing of some motor units is likely to result in phase cancellation and, therefore, the MEP amplitude, and to a lesser extent area, do not accurately reflect the net motor output.

Crossed inhibition in the human motor system.

We used transcranial magnetic stimulation in humans to investigate the effect of focal unilateral stimulation of the motor cortex on the function of the contralateral motor cortex. Surface-recorded, rectified, averaged electromyography (EMG) showed relative silent periods in small hand muscles at 35-64 and 123-158 ms following ipsilateral cortical stimulation over the hand area. The first inhibitory phase started 11 ms after the minimum corticospinal conduction time from the contralateral cortex, appropriate for transcallosal conduction. Foot muscles (with focal stimulation over the ipsilateral hand area) also showed silent periods at 61-104 ms, indicating a marked spread of the inhibitory effect throughout the opposite motor cortex. H-reflex studies in the upper limb showed that this inhibitory effect was not mediated at the level of the alpha motoneuron. Single motor unit peristimulus time histogram studies in upper limb muscles showed inhibition similar to that seen in the surface recordings and no evidence of excitation following ipsilateral motor cortex stimulation. Transcranial magnetic stimulation performed with large circular coils centered at the vertex activates both excitatory and inhibitory processes bilaterally so that focal unilateral stimulation is preferable in detailed studies of motor system physiology.

Quantitative studies of F responses in Guillain-Barré syndrome and chronic inflammatory demyelinating polyneuropathy.

We examined F wave mean and minimum latency, mean and maximum amplitude, duration, persistence and chronodispersion in 241 nerves from 78 patients with Guillain-Barré syndrome (GBS) and 162 nerves from 43 patients with chronic inflammatory demyelinating polyneuropathy (CIDP). Results were compared with normal criteria derived from 72 median, 73 ulnar and 73 tibial control nerves, to determine the relative diagnostic sensitivity of the various F wave parameters. F wave abnormalities were found in 92% and 95% of nerves of patients with GBS and CIDP respectively. Absence of F responses or prolongation of minimum and mean latency were the most frequent abnormalities in both groups. Forty-five (11.2%) nerves overall had absent F responses with normal compound muscle action potential (CMAP) amplitudes and no significant fall between stimulus sites, consistent with isolated proximal conduction block. Forty-four nerves (23.7% of nerves in which F waves were present) fulfilled minimum F latency criteria for acquired demyelination . Eighty-one (20.1%) nerves had normal conventional motor nerve conduction studies and abnormal F responses, not all of which were identified by assessing only F absence or minimum latency. Severity of F wave abnormalities did not correlate with clinical outcome. Our findings confirm the high frequency of proximal nerve lesions in early GBS and CIDP, not all of which are associated with distal motor conduction abnormalities, and suggest that assessment of multiple F wave parameters, in particular chronodispersion, mean latency and mean amplitude (in addition to absence and minimum latency), increases the yield of F wave studies.

Quantitative analysis of the compound muscle action potential in early acute inflammatory demyelinating polyneuropathy.

We quantitated the size and configuration of compound muscle action potentials (CMAPs) in 266 nerves (66 median, 67 ulnar, 71 tibial and 62 peroneal) of 72 patients with acute inflammatory demyelinating polyneuropathy (AIDP) initially studied within 19 days of symptom onset. Results were compared with criteria for CMAP abnormalities, including criteria for abnormal negative peak duration and desynchronisation, derived from a control population of 50 median, ulnar, tibial and peroneal nerves. Other motor conduction abnormalities including minimal F response latency were also examined. We also analysed patterns of CMAP abnormality, peak disability and outcome for AIDP patients who had at least 3 motor nerves evaluated at first electrophysiologic study. Amongst AIDP nerves, low amplitude of the distal CMAP, usually with prolonged distal latency, was much more common than an abnormal fall in CMAP amplitude between stimulus sites. Using our CMAP criteria more than half of these low amplitude distal responses showed prolonged negative peak duration of desynchronisation or both, consistent with demyelination. Of the 47 AIDP patients who had 3 or more nerves initially studied, 37 (78.7%) had at least 1 motor nerve with a distal CMAP showing evidence of temporal dispersion. In addition, those with at least 75% of motor nerves showing a pattern of low amplitude of the distal CMAP without a further significant fall in amplitude between stimulus sites had greater peak disability and a poorer outcome. Assessment of temporal dispersion of the distal CMAP should be included in electrophysiologic criteria for acute demyelination. In addition, for some patients with AIDP patterns of CMAP amplitude abnormality amongst motor nerves are present early in the illness and may provide prognostic information.

Effects of routine hyperventilation on PCO2 and PO2 in normal subjects: implications for EEG interpretations.

There are few data in the EEG literature describing the time course of hyperventilation-(HV) induced changes in blood gases, despite this being a routine activating procedure. We studied changes in blood gases and EEG in nine normal adult subjects before, during, and after HV. The mean PCO2 fell 18 mm Hg from the baseline during HV and recovered in 7 min. The mean PO2 rose 7 mmHg during HV and fell to 25 mm Hg below baseline 5 min after HV. The PCO2 recovery period is longer than is usually assumed in clinical EEG. The PO2 fall to a nadir at 5 min after the end of HV suggests that close attention should be paid to this period, as is confirmed by the re-buildup seen in moyamoya disease. Despite uniform changes in blood gases, the EEG median power frequency change showed marked variability; on average, it dropped by 1 Hz during HV and returned to baseline within 2 min of resumption of normal respiration. The EEG root-mean-square power showed a 200% increase during HV and also had returned to normal within 2 min.

Facilitation of magnetic motor evoked potentials during the cortical stimulation silent period.

We investigated the relationship between stimulus intensity and magnetic motor evoked potentials (MEPs) elicited 100 msec after a conditioning stimulus that was 25% of stimulator output above resting motor threshold (RMT) during tonic contraction of abductor pollicis brevis. In five subjects, MEPs elicited with stimuli less than 25% above RMT were inhibited during the EMG cortical stimulation silent period (CSSP) produced by the conditioning stimulus, relative to MEPs elicited with the test stimulus given at rest. However, increasing the intensity of the test stimulus increased the amplitude of MEPs elicited during the CSSP relative to MEPs elicited at rest, such that MEPs elicited with stimuli 30 to 45% above RMT were facilitated during the CSSP. Increasing the intensity of the test stimulus also increased the amplitude of MEPs elicited with paired stimulation at rest, and caused facilitation in one subject. Since facilitation of MEPs was never accompanied by shortening of MEP latency, our observations point to supraspinal facilitory mechanisms. We suggest that facilitation of MEPs during the CSSP reflects temporal and spatial summation of conditioning and test stimuli.

Variability of motor potentials evoked by transcranial magnetic stimulation.

We studied the effect of stimulus intensity, coil size, mental alertness and prestimulus muscle contraction on the variability of motor evoked potentials (MEPs) produced by magnetic cortical stimulation (MCS). In 5 healthy subjects we delivered MCS either with a circular coil centered at the vertex or a figure-8 coil centered over the motor cortex hand area, recording from first dorsal interosseous. With the subject at rest or exerting 5% maximum voluntary contraction, 30 consecutive stimuli were given at 4 stimulus intensities (SIs) in 10% increments above resting motor threshold. Concurrent mental arithmetic constituted mental alertness. Spectral analysis was performed on data from 300 consecutive stimuli. The variability of MEP response size was inversely related to stimulus intensity, prestimulus voluntary muscle contraction, the recruitment of motoneurons and the size of the field generated by the magnetic coil. The MEP variability was larger than and not correlated with the variability of the H-reflex. Fast Fourier transformation and cross-correlation analysis did not identify a consistent dominant frequency, suggesting that the variability in MEP size is essentially random. We suggest that the variability in MEP response is caused by constant, rapid, spontaneous fluctuations in corticospinal and segmental motoneuron excitability levels. Any maneuver that raises this level or increases the probability of motoneuron firing will decrease MEP variability.