The cortical neurophysiological signature of amyotrophic lateral sclerosis.

The progressive loss of motor function characteristic of amyotrophic lateral sclerosis is associated with widespread cortical pathology extending beyond primary motor regions. Increasing muscle weakness reflects a dynamic, variably compensated brain network disorder. In the quest for biomarkers to accelerate therapeutic assessment, the high temporal resolution of magnetoencephalography is uniquely able to non-invasively capture micro-magnetic fields generated by neuronal activity across the entire cortex simultaneously. This study examined task-free magnetoencephalography to characterize the cortical oscillatory signature of amyotrophic lateral sclerosis for having potential as a pharmacodynamic biomarker. Eight to ten minutes of magnetoencephalography in the task-free, eyes-open state was recorded in amyotrophic lateral sclerosis (n = 36) and healthy age-matched controls (n = 51), followed by a structural MRI scan for co-registration. Extracted magnetoencephalography metrics from the delta, theta, alpha, beta, low-gamma, high-gamma frequency bands included oscillatory power (regional activity), 1/f exponent (complexity) and amplitude envelope correlation (connectivity). Groups were compared using a permutation-based general linear model with correction for multiple comparisons and confounders. To test whether the extracted metrics could predict disease severity, a random forest regression model was trained and evaluated using nested leave-one-out cross-validation. Amyotrophic lateral sclerosis was characterized by reduced sensorimotor beta band and increased high-gamma band power. Within the premotor cortex, increased disability was associated with a reduced 1/f exponent. Increased disability was more widely associated with increased global connectivity in the delta, theta and high-gamma bands. Intra-hemispherically, increased disability scores were particularly associated with increases in temporal connectivity and inter-hemispherically with increases in frontal and occipital connectivity. The random forest model achieved a coefficient of determination (R2) of 0.24. The combined reduction in cortical sensorimotor beta and rise in gamma power is compatible with the established hypothesis of loss of inhibitory, GABAergic interneuronal circuits in pathogenesis. A lower 1/f exponent potentially reflects a more excitable cortex and a pathology unique to amyotrophic lateral sclerosis when considered with the findings published in other neurodegenerative disorders. Power and complexity changes corroborate with the results from paired-pulse transcranial magnetic stimulation. Increased magnetoencephalography connectivity in worsening disability is thought to represent compensatory responses to a failing motor system. Restoration of cortical beta and gamma band power has significant potential to be tested in an experimental medicine setting. Magnetoencephalography-based measures have potential as sensitive outcome measures of therapeutic benefit in drug trials and may have a wider diagnostic value with further study, including as predictive markers in asymptomatic carriers of disease-causing genetic variants.

Limited value of serum neurofilament light chain in diagnosing amyotrophic lateral sclerosis.

A biomarker specific for the diagnosis of amyotrophic lateral sclerosis must be sensitive across a spectrum of clinical heterogeneity. Neurofilament light chain levels in amyotrophic lateral sclerosis correlate with the rate of disability progression. Previous attempts to establish a diagnostic role for neurofilament light chain have been limited to comparison with healthy individuals or controls with alternative diagnoses unlikely to be confused with amyotrophic lateral sclerosis in real-world clinical practice. In a tertiary amyotrophic lateral sclerosis referral clinic, at first visit, serum was taken for neurofilament light chain measurement after prospectively recording the clinical diagnosis as 'amyotrophic lateral sclerosis', 'primary lateral sclerosis', 'alternative' or 'currently uncertain'. Of 133 referrals, 93 patients were diagnosed with amyotrophic lateral sclerosis (median neurofilament light chain 218.1 pg/ml, interquartile range 130.7-311.9), three primary lateral sclerosis (65.6, 51.5-106.9) and 19 alternative diagnoses (45.2, 13.5-71.9) at first visit. Of 18 initially uncertain diagnoses, eight were subsequently diagnosed with amyotrophic lateral sclerosis (98.5, 45.3-300.1). Neurofilament light chain ≥110.9 pg/ml had a positive predictive value of 0.92 for amyotrophic lateral sclerosis; <110.9 pg/ml had a negative predictive value of 0.48. In a specialized clinic, neurofilament light chain is largely confirmatory to clinical judgement in diagnosing amyotrophic lateral sclerosis and has limited ability to exclude alternative diagnoses. The current, important, value of neurofilament light chain is its potential to stratify patients with amyotrophic lateral sclerosis by disease activity and as a biomarker in therapeutic trials.

Neurological update: structural and functional imaging in epilepsy surgery.

Structural and functional imaging prior to surgery in drug-resistant focal epilepsy, has an important role to play alongside electroencephalography (EEG) techniques, in planning the surgical approach and predicting post-operative outcome. This paper reviews the role of structural and functional imaging of the brain, namely computed tomography (CT), magnetic resonance imaging (MRI), functional MRI (fMRI), single photon emission computed tomography (SPECT) and positron emission tomography (PET) imaging in the preoperative work-up of people with medically refractory epilepsy. In MRI-negative patients, the precise localisation of the epileptogenic zone may be established by demonstrating hypometabolism on PET imaging or hyperperfusion on SPECT imaging in the area surrounding the seizure focus. These imaging modalities are far less invasive than intracranial EEG, which is the gold standard but requires surgical placement of electrodes or recording grids. Even when intracranial EEG is needed, PET or SPECT imaging can assist in the planning of EEG electrode placement, due to its' limited spatial sampling. Multimodal imaging techniques now allow the multidisciplinary epilepsy surgery team to identify and better characterise focal pathology, determine its' relationship to eloquent areas of the brain and the degree of interconnectedness within both physiological and pathological networks, as well as improve planning and surgical outcomes for patients. This paper will update the reader on this whole field and provide them with a practical guide, to aid them in the selection of appropriate investigations, interpretation of the findings and facilitating patient discussions in individuals with drug-resistant focal epilepsy.

Bedside and laboratory diagnostic testing in myasthenia.

Myasthenia gravis (MG) and congenital myasthenic syndromes (CMS) are a group of disorders with a well characterised autoimmune or genetic and neurophysiological basis. We reviewed the literature from the last 20 years assessing the utility of various neurophysiological, immunological, provocative and genetic tests in MG and CMS. Diagnostic sensitivity of repetitive nerve stimulation test ranges between 14 and 94% and specificity between 73 and 100%; sensitivity of single-fibre EMG (SFEMG) test ranges between 64 and 100% and specificity between 22 and 100%; anti-acetylcholine receptor (AChR) antibody sensitivity ranges from 13 to 97% and specificity ranges from 95 to 100%. Overall, SFEMG has the highest sensitivity while positive anti-AChR antibodies have the highest specificity. Newer testing strategies that have been investigated over the last couple of decades include ocular vestibular-evoked myogenic potentials, otoacoustic emissions and disease-specific circulating miRNAs in serum for autoimmune myasthenia, as well as next-generation sequencing for genetic testing of CMS. While there has been significant progress in developing newer testing strategies for diagnosing MG and CMS over the last couple of decades, more research is needed to assess the utility of these newer tools regarding their sensitivity and specificity.

An unusual cause of isolated secondary ovarian failure due to cerebral toxoplasmosis in an African woman with AIDS.

Primary ovarian failure is common. However, isolated secondary ovarian failure due to gonadotrophin deficiency is rare. A few cases of isolated gonadotrophin deficiency, due to congenital cerebral toxoplasmosis, have been described in children. We report the case of a 34-year-old African woman positive for HIV, who developed secondary amenorrhoea following the successful treatment of cerebral toxoplasmosis. Investigations revealed that she developed an isolated gonadotrophin deficiency due to pituitary lesion. The rest of the pituitary function dynamic tests were normal.

Acute recurrent lymphocytic meningitis in an immunocompetent HIV-positive African woman: Is it a Mollaret's meningitis or not?

We report a case of acute recurrent meningitis in an HIV-positive immunocompetent woman. In this case, a 34-year-old African woman with a known HIV infection presented with symptoms of acute meningitis. She was on combination antiretroviral therapy with abacavir, lamivudine, and nevirapine. Her HIV RNA level was <70 IU/mL, and CD4 counts were 640 cells/mm3. This indicates that she was not immunocompromised. She was febrile on examination, with marked neck stiffness. Her cerebrospinal fluid revealed raised white cell counts with 100% lymphocytes and mildly raised protein. Polymerase chain reaction confirmed herpes simplex type 2 meningitis. She recovered fully with aciclovir 800 mg three times a day. However, she was readmitted with a similar presentation 5 months after the initial admission. Her cerebrospinal fluid confirmed recurrent herpes simplex type 2 meningitis. This case alerts the profession to the possibility of non-opportunistic infections in an immunocompetent HIV-positive patient and of herpes simplex virus type 2 causing recurrent lymphocytic meningitis.

Perforation of the bowel due to cytomegalovirus infection in a man with AIDS: surgery is not always necessary!

Cytomegalovirus (CMV) infection is the most common viral opportunistic infection in immunocompromised patients and is a rare cause of bowel perforation. It invariably requires surgical intervention and is often fatal. We report a 50-year-old Caucasian man with AIDS, presented 3 weeks after developing abdominal pain and distension. He was treated for CMV retinitis in the past. His adherence to antiretroviral therapy was poor. Examination revealed a recurrence of active CMV retinitis. His abdomen was tender and distended. The plain X-ray of the abdomen revealed a double wall sign (Rigler's sign), indicating pneumoperitoneum due to the bowel perforation. The upper endoscopy was normal. His CD4 count was 30 cells/mm(3) He was treated with cidofovir infusion. He made a full recovery, without requiring any form of surgery. However, he died of adult respiratory distress syndrome 14 months later, due to iatrogenic acute pancreatitis.

Remission of progressive multifocal leukoencephalopathy following highly active antiretroviral therapy in a man with AIDS.

A 43-year-old Caucasian homosexual man with AIDS presented with blurring of vision, change of personality, and memory loss in March 1999. He had first been admitted 2 months previously for treatment of Pneumocystis jiroveci pneumonia. A magnetic resonance imaging scan on admission showed multiple white matter lesions involving both subcortical cerebral hemispheres and cerebellar regions, with no mass effect or surrounding edema. JC virus was detected by nested polymerase chain reaction in the cerebrospinal fluid. These findings were diagnostic of progressive multifocal leukoencephalopathy (PML). His CD4 count was 34 cells/mL, and his HIV ribonucleic acid level was 800,789 copies/mL. He was treated with a combination antiretroviral therapy. He was last reviewed in October 2011. He was fully independent socially and mentally, but he still had some residual neurologic signs with right-sided homonymous hemianopia and visual agnosia. His HIV ribonucleic acid level was undetectable, and his CD4 count was 574 cells/mm(3). Although the median survival of patients with PML was poor before the antiretroviral therapy era, our patient, who is now aged 55 years, is still alive 12 years after the diagnosis. The diagnosis of PML and differential diagnosis of focal neurologic signs in HIV-positive patients are discussed in this case report.