Primary central nervous system vasculitis and headache: Ten themes.

PURPOSE OF REVIEW: The primary central nervous system (CNS) vasculitides refers to clinicopathologic disorders that share the histopathology of inflammation of cerebral or spinal blood vessels. Unrecognized and therefore untreated, vasculitis of the CNS results in irreversible injury and disability making these disorders of paramount importance to clinicians. RECENT FINDINGS: Headache is an important clue to vasculitic involvement of CNS vessels. CNS vasculitis can be primary, in which only intracranial or spinal vessels are involved in the inflammatory process, or secondary to another known disorder with overlapping systemic involvement. The suspicion of vasculitis based on the history, clinical examination, and laboratory studies warrants prompt evaluation and treatment to prevent cerebral ischemia or infarction. SUMMARY: Primary CNS vasculitides can be diagnosed with certainty after intensive evaluation that includes tissue confirmation whenever possible. As in its systemic counterparts, clinicians must choose from among the available immune modulating, suppressive, and targeted immunotherapies to induce and maintain remission status and prevent relapse, tempered by anticipated medication adverse effects.

Systemic vasculitis and headache.

PURPOSE OF REVIEW: Vasculitis refers to heterogeneous clinicopathologic disorders that share the histopathology of inflammation of blood vessels. Unrecognized and therefore untreated, vasculitis of the nervous system or so called neurovasculitides, lead to pervasive injury and disability making these disorder of paramount importance to clinicians. RECENT FINDINGS: Headache is an important clue to vasculitic involvement of central nervous system (CNS) vessels. CNS vasculitis may be primary, in which only intracranial vessels are involved in the inflammatory process, or secondary to another known disorder with overlapping systemic involvement. A suspicion of vasculitis based on the history, clinical examination, or laboratory studies warrants prompt evaluation and treatment to forestall progression and avert cerebral ischemia or infarction. There has been remarkable progress in the pathogenesis, diagnosis, and treatment of primary adult and pediatric CNS vasculitides predicated on achievements in primary systemic forms. SUMMARY: Vasculitis can be diagnosed with certainty after intensive evaluation that includes tissue confirmation whenever possible. Clinicians must choose from among the available immune modulating, suppressive, and targeted immunotherapies to induce and maintain remission status and prevent relapse, tempered by the recognition of anticipated medication side effects.

Coronavirus 2019: clinical and neuropathological aspects.

PURPOSE OF REVIEW: To understand the role of postinfectious autoimmune vascular inflammation in the pathogenesis of coronavirus disease 2019-related neurological illness caused by the novel severe acute respiratory syndrome coronavirus 2 virus and its effects on the brain in children and adults. RECENT FINDINGS: There are a very small number of postmortem neuropathological series of coronavirus disease 2019-related cerebrovascular and parenchymal disease. However, they fall into at least three major categories, with the majority manifesting those of terminal hypoxia, and others demonstrating inflammatory vascular leptomeningeal, cerebral and brainstem interstitial changes suspicious for encephalitis in a minority of cases. It remains uncertain whether these histopathological features have a relationship to post-infectious inflammatory immune mechanisms and microscopic vasculitis in adults as it appears to be in affected children with multisystem inflammatory syndrome. SUMMARY: The reasons for this dichotomy are unclear but may related to inherent and epigenetic factors that remain poorly understood. Treatment addressing postinfectious mechanisms of pulmonary, systemic, and nervous system injury may avert early mortality.

Cerebral vasculitis associated with drug abuse.

PURPOSE OF REVIEW: To review understand the epidemiology, background, neuropharmacology, and histopathology of literature verified cases, and likely etiopathogenic mechanisms. RECENT FINDINGS: There are only a handful of histologically confirmed patients in the literature with cerebral vasculitis because of drug abuse. SUMMARY: There is little justification for invasive laboratory investigation given the ready availability of highly accurate vascular neuroimaging techniques to dictate management, which usually rests upon avoidance of further exposure and minimizing the secondary neurotoxic effects of the abused substances and polypharmacy use.

Headaches and Vasculitis.

Vasculitis refers to heterogeneous clinicopathologic disorders that share the histopathology of inflammation of blood vessels. Unrecognized and therefore untreated, vasculitis of the nervous system leads to pervasive injury and disability making this a disorder of paramount importance to all clinicians. Headache may be an important clue to vasculitic involvement of central nervous system (CNS) vessels. CNS vasculitis may be primary, in which only intracranial vessels are involved in the inflammatory process, or secondary to another known disorder with overlapping systemic involvement. Primary neurologic vasculitides can be diagnosed with assurance after intensive evaluation that incudes tissue confirmation whenever possible.

Multiple sclerosis: Motor dysfunction.

Multiple sclerosis is a chronic neurological disease characterized by inflammation and degeneration within the central nervous system. Over the course of the disease, most MS patients successively accumulate inflammatory lesions, axonal damage, and diffuse CNS pathology, along with an increasing degree of motor disability. While the pharmacological approach to MS targets inflammation to decrease relapse rates and relieve symptoms, disease-modifying therapy and immunosuppressive medications may not prevent the accumulation of pathology in most patients leading to long-term motor disability. This has been met with recent interest in promoting plasticity-guided concepts, enhanced by neurophysiological and neuroimaging approaches to address the preservation of motor function.

Paraneoplastic motor disorders.

Paraneoplastic neurological disorders (PNDs) are heterogeneous clinicopathologic syndromes that occur throughout the neuraxis resulting from damage to organs or tissues remote from the site of a malignant neoplasm or its metastases. The discordance between severe neurological disability and even an indolent malignancy suggests an underlying neuroimmunologic host immune response that inflicts nervous tissue damage while inhibiting malignant tumor growth. Motor system involvement, like other symptoms and signs, is associated with focal or diffuse involvement of the brain, spinal cord, peripheral nerve, neuromuscular junction or muscle, alone or in combination due to an underlying neuroimmune and neuroinflammatory process targeting neural-specific antigens. Unrecognized and therefore untreated, PNDs are often lethal making early detection and aggressive treatment of paramount importance. While the combination of clinical symptoms and signs, and analysis of detailed body and neuroimaging, clinical neurophysiology and electrodiagnostic studies, and tumor and nervous system tissue biopsies are all vitally important, the certain diagnosis of a PND rests with the discovery of a corresponding neural-specific paraneoplastic autoantibody in the blood and/or spinal cerebrospinal fluid.

Spinal cord motor disorders.

Spinal cord diseases are frequently devastating due to the precipitous and often permanently debilitating nature of the deficits. Spastic or flaccid paraparesis accompanied by dermatomal and myotomal signatures complementary to the incurred deficits facilitates localization of the insult within the cord. However, laboratory studies often employing disease-specific serology, neuroradiology, neurophysiology, and cerebrospinal fluid analysis aid in the etiologic diagnosis. While many spinal cord diseases are reversible and treatable, especially when recognized early, more than ever, neuroscientists are being called to investigate endogenous mechanisms of neural plasticity. This chapter is a review of the embryology, neuroanatomy, clinical localization, evaluation, and management of adult and childhood spinal cord motor disorders.

Motor sequela of adult and pediatric stroke: Imminent losses and ultimate gains.

Stroke is the leading cause of neurological disability in the United States and worldwide. Remarkable advances have been made over the past 20 years in acute vascular treatments to reduce infarct size and improve neurological outcome. Substantially less progress has been made in the understanding and clinical approaches to neurological recovery after stroke. This chapter reviews the epidemiology, bedside examination, localization approaches, and classification of stroke, with an emphasis on motor stroke presentations and management, and promising research approaches to enhancing motor aspects of stroke recovery.

Pediatric neuropsychiatric disorders with motor and nonmotor phenomena.

The concept of pediatric autoimmune neuropsychiatric disorders associated with group A beta-hemolytic streptococcus (PANDAS) has become seminal since first introduced more than two decades ago. At the time of this writing, most neurologists, pediatricians, psychiatrists, and general pediatricians will probably have heard of this association or treated an affected child with PANDAS. The concept of an acute-onset, and typically self-limited, postinfectious autoimmune neuropsychiatric disorder resembling PANDAS manifesting vocal and motor tics and obsessive-compulsive disorder has broadened to other putative microbes and related endogenous and exogenous disease triggers. These disorders with common features of hypometabolism in the medial temporal lobe and hippocampus in brain 18fluorodeoxyglucose positron emission tomography fused to magnetic resonance imaging (FDG PET-MRI), form a spectrum: with the neuropsychiatric disorder Tourette syndrome and PANDAS with its well-defined etiopathogenesis at one end, and pediatric abrupt-onset neuropsychiatric syndrome (PANS), alone or associated with specific bacterial and viral pathogens, at the other end. The designation of PANS in the absence of a specific trigger, as an exclusionary diagnosis, reflects the current problem in nosology.

Mild traumatic brain injury and sports-related concussion.

Mild traumatic brain injury (mTBI) and concussion are equivalent terms for the sequela of injury to the head that disrupts brain functioning. Various forces may be causative from seemingly innocuous bumps to the head resulting from sports-related injuries to more severe blows to the head. However, the postconcussive motor, cognitive, emotional, and psychosocial sequelae can be just as devastating and long lasting, leading to loss of independent function and safe performance of activities. Taken together, they pose a significant challenge to recovery, requiring a multifaceted dynamic rehabilitative strategy. The current systems of health care pose challenges to suboptimal management of sports-related concussion (SRC) that goes beyond the acute injury, and into the school setting, failing to be identified by school staff, and inconsistencies in communicating medical information regarding school modifications, follow-up health services, or concussion-related educational services. Children who sustain SRC at different ages face different challenges. Young children face increased vulnerability due to SRC that coincides with periods of brain motor maturation and development.

COVID-19 (novel SARS-CoV-2) neurological illness.

COVID-19 illness is associated with diverse neurological manifestations. Its exceptionally high prevalence results from unprecedented genetic diversity, genomic recombination, and superspreading. With each new mutation and variant, there are foreseeable risks of rising fatality and novel neurological motor complications in childhood and adult cases. This chapter provides an extensive review of COVID-19 neurological illness, notably the motor manifestations. Innovative treatments have been developed to stem the spread of infectious contagious illness, and attenuate the resultant cytokine storm and other postinfectious immune aspects responsible for postacute COVID-19 syndrome due to the multiplier effect of infection, immunity, and inflammation, termed I3.

Neurogenetic motor disorders.

Advances in the field of neurogenetics have practical applications in rapid diagnosis on blood and body fluids to extract DNA, obviating the need for invasive investigations. The ability to obtain a presymptomatic diagnosis through genetic screening and biomarkers can be a guide to life-saving disease-modifying therapy or enzyme replacement therapy to compensate for the deficient disease-causing enzyme. The benefits of a comprehensive neurogenetic evaluation extend to family members in whom identification of the causal gene defect ensures carrier detection and at-risk counseling for future generations. This chapter explores the many facets of the neurogenetic evaluation in adult and pediatric motor disorders as a primer for later chapters in this volume and a roadmap for the future applications of genetics in neurology.

On the path to evidence-based therapy in neuromuscular disorders.

Neuromuscular disorders encompass a diverse group of acquired and genetic diseases characterized by loss of motor functionality. Although cure is the goal, many therapeutic strategies have been envisioned and are being studied in randomized clinical trials and entered clinical practice. As in all scientific endeavors, the successful clinical translation depends on the quality and translatability of preclinical findings and on the predictive value and feasibility of the clinical models. This chapter focuses on five exemplary diseases: childhood spinal muscular atrophy (SMA), Charcot-Marie-Tooth (CMT) disorders, chronic inflammatory demyelinating polyradiculoneuropathy (CIDP), acquired autoimmune myasthenia gravis (MG), and Duchenne muscular dystrophy (DMD), to illustrate the progress made on the path to evidenced-based therapy.

Neonatal and infantile hypotonia.

The underlying etiology of neonatal and infantile hypotonia can be divided into primary peripheral and central nervous system and acquired or genetic disorders. The approach to identifying the likeliest cause of hypotonia begins with a bedside assessment followed by a careful review of the birth history and early development and family pedigree and obtaining available genetic studies and age- and disease-appropriate laboratory investigations. Until about a decade ago, the main goal was to identify the clinical signs and a battery of basic investigations including electrophysiology to confirm or exclude a given neuromuscular disorder, however the availability of whole-exome sequencing and next generation sequencing and transcriptome sequencing has simplified the identification of specific underlying genetic defect and improved the accuracy of diagnosis in many related Mendelian disorders.

Childhood muscular dystrophies.

Infancy- and childhood-onset muscular dystrophies are associated with a characteristic distribution and progression of motor dysfunction. The underlying causes of progressive childhood muscular dystrophies are heterogeneous involving diverse genetic pathways and genes that encode proteins of the plasma membrane, extracellular matrix, sarcomere, and nuclear membrane components. The prototypical clinicopathological features in an affected child may be adequate to fully distinguish it from other likely diagnoses based on four common features: (1) weakness and wasting of pelvic-femoral and scapular muscles with involvement of heart muscle; (2) elevation of serum muscle enzymes in particular serum creatine kinase; (3) necrosis and regeneration of myofibers; and (4) molecular neurogenetic assessment particularly utilizing next-generation sequencing of the genome of the likeliest candidates genes in an index case or family proband. A number of different animal models of therapeutic strategies have been developed for gene transfer therapy, but so far these techniques have not yet entered clinical practice. Treatment remains for the most part symptomatic with the goal of ameliorating locomotor and cardiorespiratory manifestations of the disease.

Congenital myopathies.

The congenital myopathies are inherited muscle disorders characterized clinically by hypotonia and weakness, usually from birth, with a static or slowly progressive clinical course. Historically, the congenital myopathies have been classified according to major morphological features seen on muscle biopsy as nemaline myopathy, central core disease, centronuclear or myotubular myopathy, and congenital fiber type disproportion. However, in the past two decades, the genetic basis of these different forms of congenital myopathy has been further elucidated with the result being improved correlation with histological and genetic characteristics. However, these notions have been challenged for three reasons. First, many of the congenital myopathies can be caused by mutations in more than one gene that suggests an impact of genetic heterogeneity. Second, mutations in the same gene can cause different muscle pathologies. Third, the same genetic mutation may lead to different pathological features in members of the same family or in the same individual at different ages. This chapter provides a clinical overview of the congenital myopathies and a clinically useful guide to its genetic basis recognizing the increasing reliance of exome, subexome, and genome sequencing studies as first-line analysis in many patients.

Autonomic failure: Clinicopathologic, physiologic, and genetic aspects.

Over the past century, generations of neuroscientists, pathologists, and clinicians have elucidated the underlying causes of autonomic failure found in neurodegenerative, inherited, and antibody-mediated autoimmune disorders, each with pathognomonic clinicopathologic features. Autonomic failure affects central autonomic nervous system components in the α-synucleinopathy, multiple system atrophy, characterized clinically by levodopa-unresponsive parkinsonism or cerebellar ataxia, and pathologically by argyrophilic glial cytoplasmic inclusions (GCIs). Two other central neurodegenerative disorders, pure autonomic failure characterized clinically by deficits in norepinephrine synthesis and release from peripheral sympathetic nerve terminals; and Parkinson's disease, with early and widespread autonomic deficits independent of the loss of striatal dopamine terminals, both express Lewy pathology. The rare congenital disorder, hereditary sensory, and autonomic neuropathy type III (or Riley-Day, familial dysautonomia) causes life-threatening autonomic failure due to a genetic mutation that results in loss of functioning baroreceptors, effectively separating afferent mechanosensing neurons from the brain. Autoimmune autonomic ganglionopathy caused by autoantibodies targeting ganglionic α3-acetylcholine receptors instead presents with subacute isolated autonomic failure affecting sympathetic, parasympathetic, and enteric nervous system function in various combinations. This chapter is an overview of these major autonomic disorders with an emphasis on their historical background, neuropathological features, etiopathogenesis, diagnosis, and treatment.

Adult and childhood vasculitis.

Vasculitis refers to heterogeneous clinicopathologic disorders that share the histopathology of inflammation of blood vessels. Unrecognized and therefore untreated, vasculitis of the nervous system leads to pervasive injury and disability, making this a disorder of paramount importance to all clinicians. There has been remarkable progress in the pathogenesis, diagnosis, and treatment of primary CNS and PNS vasculitides, predicated on achievement in primary systemic forms. Primary neurological vasculitides can be diagnosed with assurance after intensive evaluation that incudes tissue confirmation whenever possible. Clinicians must choose from among the available immune modulating, suppressive, and targeted immunotherapies to induce and maintain remission status and prevent relapse, unfortunately without the benefit of RCTs, and tempered by the recognition of anticipated medication side effects. It may be said that efforts to define a disease are attempts to understand the very concept of the disease. This has been especially evident in systemic and neurological disorders associated with vasculitis. For the past 100 years, since the first description of granulomatous angiitis of the brain, the CNS vasculitides have captured the attention of generations of clinical investigators around the globe to reach a better understanding of vasculitides involving the central and peripheral nervous system. Since that time it has become increasingly evident that this will necessitate an international collaborative effort.