Graeme Hammond-Tooke

Transforming growth factor-β2 is elevated in skeletal muscle disorders

The transforming growth factor betas (TGF‐βs) are multifunctional growth factors that act on both fibroblasts and myosatellite cells. In rodent models of muscle diseases, high levels of TGF‐β2 are expressed by myogenic cells. We have examined whether the expression of TGF‐β2 is also elevated in diseased human muscles. The disorders examined were Duchenne muscular dystrophy, myotonic dystrophy, myotubular myopathy, spinal muscular atrophy, and amyotrophic lateral sclerosis. The levels of TGF‐β2 immunoreactivity were elevated in atrophic, necrotic, and regenerating fibers and in fibers with central nuclei or cytoplasmic masses, irrespective of whether fibrosis was present. We therefore suggest that TGF‐β2 is important for muscle repair and that the presence of a TGF‐β within a muscle only leads to fibrosis if certain other factors are present.

Normative values for three clinical measures of motor performance used in the neurological assessment of sports concussion.

Postural control and motor coordination are essential components of normal athletic activity. Tasks involving balance and coordination are used to determine neurological function in sports-related concussion. Determining normative values for these tasks is therefore essential to provide sports medicine professionals with a frame of reference with which to interpret clinical measures obtained from players suspected of sustaining a concussion. One hundred and seventytwo healthy subjects (16-37 yrs) performed three timed tests: Tandem Gait (TG); Finger-to-Nose (FTN); Single-Leg-Stance (SLS) on firm and foam surfaces. Unadjusted geometric means (+/-SD) for each measure were averaged across three trials. Time to complete TG was 11.2+/-1.2s. FTN for the dominant and non-dominant arm were 2.9+/-1.1s and 3.0+/-1.2s, respectively. SLS values for dominant and non-dominant leg were 20.4+/-3.0s (firm), 3.4+/-1.6s (foam), and 21.0+/-2.9s (firm), 3.3+/-1.6s (foam), respectively. For TG, there was an order effect (P<.001) but no age, sex or BMI effects. FTN demonstrated a dominant arm preference (P<.001), sex (P=.006), BMI (P=.043) and order effects (P<.001). SLS demonstrated an order effect on the firm surface (P=.009) and an order (P<.001) and BMI (P=.001) effect on foam. Intra-rater reliability, as measured by ICC (3,3), demonstrated that TG and FTN had excellent reliability compared to SLS. FTN and TG should continue to be used in test batteries to determine neurological function in sports-related concussion.

STIR MRI to direct muscle biopsy in suspected idiopathic inflammatory myopathy.

Successful management of the idiopathic inflammatory myopathies requires an early and accurate diagnosis. The muscle biopsy remains the definitive test. However, false-negative biopsy results are common, as the disease is typically patchy in distribution. The advent of short tau inversion recovery sequences now allows rapid magnetic resonance imaging of the whole body to be performed, enabling identification of the muscles most suitable for biopsy. It also provides further diagnostic information through the form and anatomic distribution of the pathology. We report 2 cases illustrating the advantages of whole-body short tau inversion recovery magnetic resonance imaging before muscle biopsy. We encourage clinicians to use the technique in this context.

Theta Burst Stimulation of the Cerebellum Modifies the TMS-Evoked N100 Potential, a Marker of GABA Inhibition.

Theta burst stimulation (TBS) of the cerebellum, a potential therapy for neurological disease, can modulate corticospinal excitability via the dentato-thalamo-cortical pathway, but it is uncertain whether its effects are mediated via inhibitory or facilitatory networks. The aim of this study was to investigate the effects of 30Hz cerebellar TBS on the N100 waveform of the TMS-evoked potential (TEP), a marker of intracortical GABAB-mediated inhibition. 16 healthy participants (aged 18–30 years; 13 right handed and 3 left handed) received 30Hz intermittent TBS (iTBS), continuous TBS (cTBS) or sham stimulation over the right cerebellum, in three separate sessions. The first 8 participants received TBS at a stimulus intensity of 80% of active motor threshold (AMT), while the remainder received 90% of AMT. Motor evoked potentials (MEP) and TEP were recorded before and after each treatment, by stimulating the first dorsal interosseus area of the left motor cortex. Analysis of the 13 right handed participants showed that iTBS at 90% of AMT increased the N100 amplitude compared to sham and cTBS, without significantly altering MEP amplitude. cTBS at 80% of active motor threshold decreased the N100 amplitude and cTBS overall reduced resting MEP amplitude. The study demonstrates effects of 30Hz cerebellar TBS on inhibitory cortical networks that may be useful for treatment of neurological conditions associated with dysfunctional intracortical inhibition.

Distinct Modulation of Event-Related Potentials during Motor Preparation in Patients with Motor Conversion Disorder

Objective Conversion paresis patients and healthy people feigning weakness both exhibit weak voluntary movement without detectable neuropathology. Uniquely, conversion patients lack a sense of conscious awareness of the origin of their impairment. We investigated whether conversion paresis patients show distinct electroencephalographic (EEG) markers associated with their unconscious movement deficits. Methods Six unilateral upper limb conversion paresis patients, 12 feigning participants asked to mimic weakness and 12 control participants performed a precued reaction time task, requiring movements of either hand, depending on precue information. Performance measures (force, reaction and movement time), and event-related EEG potentials (ERP) were compared, between groups and across hands or hemisphere, using linear mixed models. Results Feigners generated the same inter-hand difference in reaction and movement time as expressed by patients, even though no specific targets were set nor feedback given on these measures. We found novel ERP signatures specific to patients. When the symptomatic hand was precued, the P3 ERP component accompanying the precue was dramatically larger in patients than in feigning participants. Additionally, in patients the earlier N1 ERP component was diminished when the precue signalled either the symptomatic or asymptomatic hand. Conclusions These results are consistent with previous suggestions that lack of awareness of the origin of their symptoms in conversion disorder patients may result from suppression of brain activity normally related to self-agency. In patients the diminished N1 to all precues is consistent with a generalised reduction in cognitive processing of movement-related precues. The P3 enhancement in patients is unlikely to simply reflect changes required for generation of impaired movements, because it was not seen in feigners showing the same behavioural deficits. Rather, this P3 enhancement in patients may represent a neural biomarker of unconscious processes, including additional emotional loading, related to active suppression of brain circuits involved in the attribution of self-agency.

The New Zealand Neuromuscular Disease Registry

The development of effective treatments for neuromuscular diseases is a significant challenge due to difficulties in identifying adequate numbers of patients for clinical trials. Low patient numbers in these rare diseases also has an effect when establishing sound clinical practices based on experience gained from patients with similar diagnosis. The Muscular Dystrophy Association of New Zealand (MDA), working in consort with interested clinicians has established the New Zealand Neuromuscular Disease (NZ NMD) Registry in order to help address these problems. The NZ NMD Registry is exceptional in that it comprises one registry for all neuromuscular conditions and will significantly benefit both patients with neuromuscular disease and their clinicians.

Clinical Features of Opticospinal Multiple Sclerosis with Anti-Aquaporin 4 Antibody

Background: We have followed 9 Japanese patients with opticospinal multiple sclerosis (OSMS), some of whom showed longitudinally extensive spinal cord lesions, deep sensory disturbances and resistance to treatment. We investigated the patients for anti-aquaporin 4 (AQP4) antibodies and related this to their neuroimaging, clinical and laboratory features. Methods: We studied the clinical course, neurological findings, cerebrospinal fluid (CSF), and electrophysiological findings, and determined the presence of anti-AQP4 antibody and human leukocyte antigen DPB1 and DRB1 alleles. Results: Five patients (56.6%) had anti-AQP4 antibody. Antibody-positive patients displayed female predominance, longitudinally extensive spinal cord lesions, higher frequency of exacerbations, severe disability, and higher cell counts and total protein content without IgG oligoclonal bands in the CSF. They also showed poor steroid responsiveness and poor therapeutic response to interferon β1b. Conclusions: The presence of anti-AQP4 antibodies correlates with clinical severity and poor prognosis in OSMS.

A Mini-Mental Status Examination for the hearing impaired

A, Delecluse C et al. Habitual level of physical activity and muscle fatigue of the elbow flexor muscles in older men. L et al. Lower extremity performance is associated with daily life physical activity in individuals with and without peripheral arterial disease. Muscle strength in the triceps surae and objectively measured customary walking activity in men and women over 65 years of age. A short physical performance battery assessing lower extremity function: association with self-reported disability and prediction of mortality and nursing home admission. The association between physical function and lifestyle activity and exercise in the health, aging and body composition study. Effect of exercise on ease in performing activities of daily living and instrumental activities of daily living from age 70 to 77: the Jerusalem longitudinal study. Rennie KL et al. Validity and repeatability of a simple index derived from the short physical activity questionnaire used in the European Prospective Investigation into Cancer and Nutrition (EPIC) study. SIR—The Folstein Mini-Mental State Examination (MMSE), developed in 1975 as a bedside test of cognitive function, has been extensively used in clinical practice and research and is widely accepted as a clinical tool for diagnosing and monitoring dementia [1]. Despite its low sensitivity and specificity (0.56 and 0.73, respectively, in one recent study) [2], comparable tools, including the Modified MMSE of Teng and Chui [3] have not received such widespread acceptance. It contains 11 questions that test orientation, registration, attention, calculation, recall, language and visuospatial functioning, with a maximum score of 30. It takes minutes to administer and is practical for routine clinical use. Most questions are administered verbally. Hearing loss reduces performance on the verbal parts of the examination even in cognitively intact patients, with potential diagnostic error and alteration of management [4]. This is of concern, as hearing impairment affects over one-fourth of people over 65 years of age, and half of those over 75 years in most industrialised nations [5]. Uhlmann [6] tested 71 Alzheimers disease subjects with varying levels of hearing, using both written and standard versions of the MMSE. Paradoxically, they found that hearing-impaired subjects scored higher in the standard than the written version, while subjects with normal hearing performed better using the written version, although these findings were not statistically significant. We (M.M.) developed a written version of the MMSE, found it clinically useful, and report here an evaluation of its performance in a hospital-based population …

The diagnostic accuracy of selected neurological tests

The diagnostic value and reliability of selected neurological clinical tests was studied in control subjects with normal neuroimaging (n=42), and subjects with a focal brain lesion (n=38). The items were studied by two examiners blinded to group membership and using standardized protocols, and subsequently by a neurologist who was not blinded to diagnosis. The positive likelihood ratios ranged from 1.06 (pronator drift) to 22.11 (single leg stance with eyes open, while the negative likelihood ratios ranged from 0.47 (tandem gait) to 0.97 (pupil symmetry). Three items (single leg stance - eyes closed - firm surface; single leg stance - eyes open - foam surface; and tandem gait) successfully distinguished between the two groups (odds ratio p<0.05). The inter-rater reliability was generally poor, with only tandem gait showing excellent agreement (kappa [K]=0.92). Tandem gait was the only item to show noteworthy agreement (K=0.93) between the examiners and the neurologist. The tests varied considerably in their ability to detect radiologically demonstrated structural brain lesions, and several items were poorly reproducible, questioning their value as part of a routine neurological examination.

Facial pain and muscle atrophy secondary to an intracranial tumour

Orofacial pain rarely arises from a distant site. It is unusual for orofacial pain to be associated with wasting of the facial musculature and diminished sensation. This case report describes a patient who presented with temporomandibular joint pain dysfunction syndrome which was initially successfully managed with splint therapy. She re-presented later with unilateral wasting of the muscles of mastication, facial pain and diminished sensation ipsilaterally. An intracranial meningioma was diagnosed following an extensive series of investigations.