Neurologic Disorders
Autoimmune Neuropathies – Neuropathic Disease
Multiple Sclerosis
Central Nervous System Tumors – Brain Tumors
Myasthenia Gravis – MG
Neuromyelitis Optica Spectrum Disorders
N-methyl-D-Aspartate (NMDA)-Type Glutamate Receptor Autoantibody Disorders – Anti-NMDA-Receptor Encephalitis
Paraneoplastic Neurological Syndromes and Associated Disorders – PNS
Postanoxic Coma – Anoxia
Thrombotic Microangiopathies – TMA
Cerebrospinal Fluid (CSF) Leak – Beta-2 Transferrin
Infectious Disease
Meningitis
Herpes simplex virus (HSV)
Human T lymphotropic virus Type I, II; HTLVI I, II
Infectious Encephalitis
Lymphocytic choriomeningitis- LCM
Treponema Pallidum- Syphilis
Autoimmune Neuropathies – Neuropathic Disease
Definition:
The immune-mediated neuropathies are a mainly group of neuropathies that often lead to severe neurologic dysfunction. Autoimmune neuropathies present with a broad range of symptom but main signs are including tingling in the feet or hands, burning, stabbing pain in affected regions, loss of balance and coordination, muscle weakness in the feet.
The overlap of symptoms among syndromes often makes diagnosis difficult. Autoimmune neuropathies can also happen as paraneoplastic disorders in the setting of cancer.
Panel Test:
Motor and Sensory Neuropathy Evaluation
Purkinje cell/neuronal nuclear IgG
neuronal nuclear (Hu, Ri, and Yo) IgG
neuronal nuclear antibody (ANNA) IgG titer
MAG IgM
SGPG Igasialo-GM1, GM1, GD1a, GD1b IgG and IgM
GQ1b abs
SPEP (Serum protein electrophoresis); immunoglobulins A, G, and M
Paraneoplastic antibodies
ANNA-1 (Hu)
ANNA-2 (Ri)
PCCA-1 (Yo),
amphiphysin,
CV2.1 antibody.
References:
Chaudhry HM, Mauermann ML, Rajkumar V. Monoclonal Gammopathy-Associated Peripheral Neuropathy: Diagnosis and Management. Mayo Clin Proc. 2017; 92(5): 838-850. PubMed
Multiple Sclerosis
Definition:
Multiple sclerosis (MS) is a chronic inflammatory disease pftem potentially disabling, demyelinating and neurodegenerative of the brain and spinal cord in young adults. This disorder is a heterogeneous, multifactorial, immune-mediated disease that is influenced by both genetic and environmental factors. Multiple sclerosis symptoms could be differing greatly in patients and over the course of the disease depending on the location and the amount of damage in affected nerve fibers. MS symptoms include visual impairments, tingling and numbness, episodic bouts of fatigue, intestinal and urinary system disorders, spasticity, and learning and memory impairment.
Panel test:
Oligoclonal Band in CSF and Serum
IgG – serum, CSF, index
Albumin – CSF, serum by nephelometry, index
CSF – IgG/albumin ratio, IgG synthesis rate, OCBs
Aquaporin-4 Receptor Antibody
Aid in evaluation of Neuromyelitis optica (NMO) and NMO spectrum disorders
Anti- myelin oligodendrocyte glycoprotein (MOG)
Interferon Beta Neutralizing Antibody
Natalizumab Antibodies
Reference:
Thompson AJ, Banwell BL, Barkhof F, Carroll WM, Coetzee T, Comi G, Correale J, Fazekas F, Filippi M, Freedman MS, Fujihara K, Galetta SL, Hartung HP, Kappos L, Lublin FD, Marrie RA, Miller AE, Miller DH, Montalban X, Mowry EM, Sorensen PS, Tintoré M, Traboulsee AL, Trojano M, Uitdehaag BM, Vukusic S, Waubant E, Weinshenker BG, Reingold SC, Cohen JA. Diagnosis of multiple sclerosis: 2017 revisions of the McDonald criteria. Lancet Neurol. 2018; 17(2): 162-173. PubMed
Central Nervous System Tumors – Brain Tumors
Definition:
Primary and metastatic brain tumors are a heterogeneous group of neoplasms with varied outcomes and management strategies. Primary brain tumors range from pilocytic astrocytomas, which are very uncommon, noninvasive, and surgically curable, to glioblastoma multiforme, the most common intraparenchymal brain tumor in adults, which is highly invasive and virtually incurable.
CNS tumors are associated with a range of symptoms and complications, such as edema, seizures, endocrinopathy, fatigue, psychiatric disorders, and venous thromboembolism, that can seriously impact quality of life.
Lab tests:
ATRX
IDH1 R132H
Ki-67 with Interpretation
Glial Fibrillary Acidic Protein (GFAP)
S-100 Protein
CD56 (NCAM)
p53 with Interpretation
CD117 (c-Kit)
Placental Alkaline Phosphatase (PLAP)
Human Chorionic Gonadotropin (Beta-hCG)
Alpha-1-Fetoprotein (AFP)
Inhibin
D2-40
Synaptophysin
References:
Louis DN, Perry A, Reifenberger G, von Deimling A, Figarella-Branger D, Cavenee WK, Ohgaki H, Wiestler OD, Kleihues P, Ellison DW. The 2016 World Health Organization Classification of Tumors of the Central Nervous System: a summary. Acta Neuropathol. 2016; 131(6): 803-20. PubMed
Myasthenia Gravis – MG
Definition:
Myasthenia gravis is a chronic neuromuscular disease in which antibodies attached to acetylcholine receptors which is critical factor for relation between nerve and muscles.
The main symptom is weakness of skeletal muscles, talking problems, problems lifting objects or arising stairs. The weakness typically increases with exercise and repetitive muscle use (fatigue) and varies over the course of a day and from day to day.
Lab tests:
Autoantibodies:
Acetylcholine receptor (AChR) antibodies: There are three types of AChR antibodies: binding (most frequently tested), blocking, and modulating.
Anti-MuSK (muscle-specific kinase) antibodies
Anti-striated muscle antibodies
Titin antibodies: Rheumatoid factor (RF)
Cyclic citrullinated peptide antibody (CCP)
Antinuclear antibody (ANA)
Thyroid panel and thyroid antibodies
Immunogenetic test:
HLA-A1, B8, DR3, HLA-Bw35/DR1 (induced by penicillamine)
Reference:
Gilhus NE. Myasthenia Gravis. N Engl J Med. 2016; 375(26): 2570-2581. PubMed
Neuromyelitis Optica Spectrum Disorders
Definition:
Neuromyelitis optica spectrum disorders (NMOSD) is an autoimmune disorder of the central nervous system and is often mistaken for multiple sclerosis (MS).
Extra optico spinal manifestations of NMOSD:
The clinical manifestations of NMOSD may involve sites outside the spinal cord and optic nerve. They may be the presenting and sometimes the only features of the disease. Brain stem involvement in the form of intractable vomiting (area postrima syndrome), intractable hiccups due to peri-aquiductal lesions in the midbrain and narcolepsy, hypothermia and hypersomnolence due to diencephalic involvement.
Non-neurological manifestations of NMO:
Recently placentitis with risk of abortion, internal otitis and gastritis have been described with seropositive NMOSD.
Lab tests:
Aquaporin-4 receptor (AQP4) Antibody
Myelin oligodendrocyte glycoprotein (MOG) Antibody
Reference:
Weinshenker BG, Wingerchuk DM. Neuromyelitis Spectrum Disorders. Mayo Clin Proc. 2017; 92(4): 663-679. PubMed
N-methyl-D-Aspartate (NMDA)-Type Glutamate Receptor Autoantibody Disorders – Anti-NMDA-Receptor Encephalitis
Definition:
Anti-N-methyl-d-aspartate (NMDA) receptor encephalitis is a form of encephalitis associated with antibodies against NR1 or NR2 subunits of the NMDA receptor.
Affected individuals typically develop prominent psychiatric symptoms, cognitive dysfunction, seizures, orofacial dyskinesias, and autonomic instability (8, 9).
Lab tests:
Panel includes:
NDMA receptor antibody
glutamic acid decarboxylase (GAD) antibody
VGKC antibody
aquaporin-4 receptor antibody
aquaporin-4 receptor antibody
LGI1 antibody
CASPR2 antibody
AMPA receptor antibody
GABA receptor antibody
MOG antibody
Voltage-gated calcium channel (VGCC) antibody
Acetylcholine receptor modulating antibody
Titin antibody
Striated muscled antibody
Reference:
Venkatesan A, Tunkel AR, Bloch KC, Lauring AS, Sejvar J, Bitnun A, Stahl J, Mailles A, Drebot M, Rupprecht CE, Yoder J, Cope JR, Wilson MR, Whitley RJ, Sullivan J, Granerod J, Jones C, Eastwood K, Ward KN, Durrheim DN, Solbrig MV, Guo-Dong L, Glaser CA, International Encephalitis Consortium. Case definitions, diagnostic algorithms, and priorities in encephalitis: consensus statement of the international encephalitis consortium. Clin Infect Dis. 2013; 57(8): 1114-28. PubMed
Paraneoplastic Neurological Syndromes and Associated Disorders – PNS
Definition:
Paraneoplastic neurologic syndromes (PNS) comprise an extensive group of heterogeneous disorders that can affect any part of the central and peripheral nervous system. There is evidence that many of these disorders are mediated by immunologic responses triggered by the presence of a cancer.
Lab tests:
Purkinje cell/neuronal nuclear IgG screen
Neuronal nuclear antibody (ANNA) IgG
Purkinje cell antibody, titer
Neuronal nuclear antibodies (Hu, Ri, Yo) IgG
Amphiphysin
Reference:
Zuliani L, Graus F, Giometto B, Bien C, Vincent A. Central nervous system neuronal surface antibody associated syndromes: review and guidelines for recognition. J Neurol Neurosurg Psychiatry. 2012; 83(6): 638-45. PubMed
Postanoxic Coma – Anoxia
Definition:
Postanoxic coma is a state of unconsciousness caused by global anoxia of the brain, most commonly due to cardiac arrest. Outcome after postanoxic coma lasting more than several hours is generally, but not invariably, poor.
Lab tests:
Neuron Specific Enolase
as a tumor marker for evaluation of neuroendocrine tumors
S-100B Protein, Serum
as a biomarker of various central nervous system (CNS) pathologies and as a tumor marker for malignant melanoma.
S100B, CSF
May be useful as a biomarker of various CNS pathologies.
Reference:
Wijdicks EF, Hijdra A, Young GB, Bassetti CL, Wiebe S, Quality Standards Subcommittee of the American Academy of Neurology. Practice parameter: prediction of outcome in comatose survivors after cardiopulmonary resuscitation (an evidence-based review): report of the Quality Standards Subcommittee of the American Academy of Neurology. Neurology. 2006; 67(2): 203-10. Reaffirmed Oct 2009. PubMed
Zandbergen EG. Postanoxic coma: how (long) should we treat? European journal of anaesthesiology Supplement. 2008;42:39-42.
Thrombotic Microangiopathies – TMA
Definition:
Thrombotic microangiopathy (TMA) is a broad pathophysiologic process that leads to microangiopathic hemolytic anemia and thrombocytopenia, and involves capillary and small-vessel platelet aggregates. The most common cause is disseminated intravascular coagulation, which may be differentiated by abnormal coagulation. Clinically, a number of conditions present with microangiopathic hemolytic anemia and thrombocytopenia, including cancer, infection, transplantation, drug use, autoimmune disease, and pre-eclampsia and hemolysis, elevated liver enzymes and low platelet count syndrome in pregnancy.
Lab tests:
ADAMTS13:
to assist in diagnosis of thrombotic thrombocytopenic purpura (TTP) and in distinguishing between inherited and acquired forms of TTP.
If ADAMTS13 activity is ≤30%, then ADAMTS13 inhibitor will be added; if ADAMTS13 inhibitor is <0.7 BU, then ADAMTS13 antibody will be added.
ADAMTS13 activity
ADAMTS13 Inhibitor: If suspicion for TTP remains after a negative result, ADAMTS13 antibody is recommended.
ADAMTS13 Antibody
Reference:
Scully M, Cataland S, Coppo P, de la Rubia J, Friedman KD, Kremer Hovinga J, et al. Consensus on the standardization of terminology in thrombotic thrombocytopenic purpura and related thrombotic microangiopathies. Journal of thrombosis and haemostasis: JTH. 2017;15(2):312-22.
Go RS, Winters JL, Leung N, Murray DL, Willrich MA, Abraham RS, Amer H, Hogan WJ, Marshall AL, Sethi S, Tran CL, Chen D, Pruthi RK, Ashrani AA, Fervenza FC, Cramer CH, Rodriguez V, Wolanskyj AP, Thomé SD, Hook C, Mayo Clinic Complement Alternative Pathway-Thrombotic Microangiopathy Disease-Oriented Group. Thrombotic Microangiopathy Care Pathway: A Consensus Statement for the Mayo Clinic Complement Alternative Pathway-Thrombotic Microangiopathy (CAP-TMA) Disease-Oriented Group. Mayo Clin Proc. 2016; 91(9): 1189-211. PubMed
Cerebrospinal Fluid (CSF) Leak -Beta-2 Transferrin
Definition:
Cerebrospinal fluid (CSF) leaks are one of the common complications after traumatic brain injuries (TBI). The risks of CSF leaks can be detrimental to the outcomes of the patients. Early diagnosis and proper management is imperative for it is strongly associated with a better long-term prognosis of the patients.
The most common clinical symptom is the leak of clear and watery drainage from the nose and ear with a positional dependency.
Lab test:
Beta-2 Transferrin
Reference:
McCudden CR, Senior BA, Hainsworth S, et al. Evaluation of high resolution gel β(2)-transferrin for detection of cerebrospinal fluid leak. Clin Chem Lab Med 2013; 51:311.
Prosser JD, Vender JR, Solares CA. Traumatic cerebrospinal fluid leaks. Otolaryngol Clin North Am 2011; 44:857.
Infectious Disease
Meningitis
Definition:
Acute bacterial meningitis is an inflammation of the meninges and subarachnoid space that can also involve the brain cortex and parenchyma. Diagnosis of meningitis is mainly based on clinical presentation and cerebrospinal fluid analysis. Fever, headache, neck stiffness, and altered mental status are classic symptoms of meningitis.
Aseptic meningitis is an inflammation of the meninges caused mainly by nonbacterial organisms, specific agents, or other disease processes. Aseptic meningitis (including viral meningitis) is the most common infection of the central nervous system (CNS) in the pediatric population, occurring most frequently in children younger than 1 year.
Distinguishing aseptic from bacterial meningitis is not always easy due to considerable overlap in clinical symptoms and laboratory findings.
Lab tests:
Encephalitis Panel include West Nile Virus (WNV), measles, mumps, VZV, HSV-1, and HSV-2
Neisseria meningitidis Tetravalent Antibodies (Serogroups A, C, W-135 and Y), IgG
West Nile Virus Antibodies, IgG and IgM
Lymphocytic Choriomeningitis (LCM) Virus Antibodies, IgG & IgM, CSF
Herpes Simplex Virus – HSV
Definition:
Herpes simplex virus (HSV) occurs worldwide and produces a variety of clinical manifestations, ranging from mild stomatitis to fatal disease. Herpes simplex virus type 2 (HSV-2) causes recurrent genital herpes episodes more often than herpes simplex virus type 1 (HSV-1), although HSV-1 is responsible for a growing number of genital herpes cases.
Lab tests:
Herpes Simplex Virus (HSV) Types I/II (Immunohistochemistry)
Herpes Simplex Type 1 and Type 2 Glycoprotein G-Specific Antibodies, IgG (chemiluminescent Immunoassay)
Human T-Lymphotropic Virus Types I, II – HTLV I, II
Definition:
Human T-cell lymphotropic virus type I (HTLV-I) is etiologically associated with adult T-cell leukemia/lymphoma (ATLL); tropical spastic paraparesis (TSP), a demyelinating neurological disorder; and HTLV-I-associated myelopathy (HAM). Two types of HTLV testing are available – antibody and molecular testing.
Lab tests:
Human T-Lymphotropic Virus (HTLV) Types I/II Antibodies (ELISA)
Human T-Lymphotropic Virus Types I/II Antibodies (Western Blot)
Infectious Encephalitis
Definition:
Encephalitis is a devastating neurologic syndrome that is characterized by inflammation of the brain parenchyma. While infectious encephalitis is most often identified, the cause remains unknown in up to 50% of cases. An acute clinical presentation may suggest more virulent viruses and bacteria, while a subacute presentation is more often associated with indolent bacteria, fungi, parasites, and autoimmune and paraneoplastic causes. More than 90% of viral encephalitis is caused by herpes simplex virus (HSV), varicella-zoster virus (VZV), and enteroviruses (Venkatesan, 2014), with typical bacterial causes of cerebritis and abscesses consisting of polymicrobial streptococci, gram-negative bacilli, and Staphylococcus aureus infections. Early recognition and treatment for HSV, bacterial, Plasmodium falciparum, and rabies infections are critical and potentially lifesaving. Diagnosis requires a combination of clinical, laboratory, and neuroimaging findings.
Lab test:
Cryptococcus antigen (CSF)
Lymphocytic Choriomeningitis – LCM
Definition:
Lymphocytic choriomeningitis (LCM) virus is spread by rodents. It can be deadly to immunocompromised patients but rarely affects healthy individuals.
Lab test:
Lymphocytic Choriomeningitis (LCM) Virus Antibodies, IgG & IgM (Serum, CSF)
Treponema pallidum – Syphilis
Definition:
Treponema pallidum subspecies pallidum is the causative agent of venereal syphilis, a sexually transmitted infection (STI). If left untreated, syphilis can result in multisystem involvement with significant morbidity. Traditional serologic screening for syphilis initially uses nontreponemal testing, with confirmation of reactive results using a treponemal test. New reverse algorithms initially use treponemal testing (usually enzyme immunoassays [EIAs] or chemiluminescence immunoassays [CIAs]), with confirmation of reactive results using a nontreponemal test. Of note, mothers infected with syphilis can pass the infection to their children in utero (congenital syphilis).
Lab tests:
Rapid Plasma Reagin (RPR)
Treponema pallidum (VDRL)
Treponema pallidum Antibody, IgG
Treponema pallidum Antibody, IgG by IFA (FTA-ABS), Serum
References:
Mount HR, Boyle SD. Aseptic and Bacterial Meningitis: Evaluation, Treatment, and Prevention. Am Fam Physician. 2017; 96(5): 314-322. PubMed
CDC STD Prevention. STD Curriculum for Clinical Educators: Genital Herpes Simplex Virus (HSV) Module. Centers for Disease Control and Prevention. Atlanta, GA [Published : Mar 2014; Accessed: Oct 2017]
US Preventive Services Task Force, Bibbins-Domingo K, Grossman DC, Curry SJ, Davidson KW, Epling JW, Garcia FA, Kemper AR, Krist AH, Kurth AE, Landefeld S, Mangione CM, Phillips WR, Phipps MG, Pignone MP, Silverstein M, Tseng C. Serologic Screening for Genital Herpes Infection: US Preventive Services Task Force Recommendation Statement. JAMA. 2016; 316(23): 2525-2530. PubMed
Tunkel AR, Glaser CA, Bloch KC, Sejvar JJ, Marra CM, Roos KL, Hartman BJ, Kaplan SL, Scheld M, Whitley RJ, Infectious Diseases Society of America. The management of encephalitis: clinical practice guidelines by the Infectious Diseases Society of America. Clin Infect Dis. 2008; 47(3): 303-27. PubMed
sukasaki K, Hermine O, Bazarbachi A, Ratner L, Ramos JC, Harrington W, O’Mahony D, Janik JE, Bittencourt AL, Taylor GP, Yamaguchi K, Utsunomiya A, Tobinai K, Watanabe T. Definition, prognostic factors, treatment, and response criteria of adult T-cell leukemia-lymphoma: a proposal from an international consensus meeting. J Clin Oncol. 2009; 27(3): 453-9. PubMed
Kang SS, McGavern DB. Lymphocytic choriomeningitis infection of the central nervous system. Front Biosci. 2008; 13: 4529-43. PubMed
Centers for Disease Control and Prevention. Morbidity and mortality weekly report (MMWR): Increase in incidence of congenital syphilis – United States, 2012-2014. CDC. Atlanta, GA [Released: Nov 2015; Accessed: Sep 2018]
