Tropical Neurology - part 5 pdf

The spectrum of parainfectious demyelinating syndromes is wideand includes the following disorders: 1 acute disseminated encephalomyelitis; 2acute hemorrhagic leukoencephalitis; 3 acute

in two or more limbs or multiple cranial nerves as opposed to limited involvement

in the early stage

The etiology of mononeuropathy multiplex in late HIV may be due to tions such as herpes zoster, cryptococcus, toxoplasma and cytomegalovirus; andneoplastics such as lymphoma and cryoglobulinaemia Treatment of mononeuropathymultiplex in late stage HIV includes antiretroviral therapy and treatment of under-lying infection If no cause can be detected, empirical treatment with gancyclovir isrecommended

infec-Progressive polyradiculopathy occurs late in the course of HIV disease, and alarge number of patients have coexisting cytomegalovirus (CMV) infection; how-ever, with effective antiretroviral therapy, the incidence of CMV-inducedpolyradiculopathy has declined Patients present with radiating pain and paresthesias

in cauda equina distribution resulting in cauda equina syndrome Radiculopathy inupper limbs occurs in the late stage of disease It has a poor prognosis with nearly100% mortality within 30 days Cerebrospinal fluid reveals raised protein and lym-phocytic pleocytosis PCR may be positive for CMV DNA Myelography and MRIdemonstrate enhancement of lumbar thecal sac or leptomeninges in conus medullaris

to cauda equina Gancyclovir with other antiretroviral drugs is used for its ment

treat-Fig 12.3a Radiography of chest showing multiple lung abscesses in a 60 year old lady with AIDS (Courtesy Prof U K Misra).

Fig 12.3b Gadolinium enhanced spinal MRI, T 1 sequence in sagittal section of the same patient as in Figure 12.3a showing cervical vertebral involvement with prevertebral soft tissue shadow due to tuberculosis (Courtesy Prof U K Misra).

Autonomic neuropathy seems to occur in late HIV disease, particularly whenother neurologic deficits are present Drugs such as tricyclic antidepressant, vincris-tine and pentamidine may contribute to autonomic dysfunction in HIV patients

On autopsy symptomatic and offending sympathetic ganglia have been found to beaffected Treatment is symptomatic and offending drugs should be withdrawn

Myopathy

Progressive proximal muscle weakness is seen in late stage of HIV and is uted to wasting, cachexia, bacterial infections and antiretroviral drugs

attrib-Opportunistic infections in HIV

Many opportunistic infections can affect the nervous system in AIDS patientswhich are mentioned in Table 12.3 Infection with HIV is associated with a broadspectrum of immune deficiency ranging from mild to severe Susceptibility for op-portunistic infections and malignancies varies with degrees of immune suppression

as indicated by peripheral blood CD4 lymphocyte counts; which are summarized inTable 12.4

Toxoplasma Encephalitis

Toxoplasma is an intracellular parasite which exists in three forms: 1) Tachyzoiteswhich causes active disease; 2) Bradyzoites responsible for latent disease; and 3)Oocyst- responsible for transmission of disease

Man acquires infection by ingesting oocyst shed in cat feces or ingestingbradyzoites in undercooked meat In immunocompetent individuals, the primaryinfection remains asymptomatic in 90% Toxoplasma encephalitis in HIV resultsdue to reactivation of latent infection in 90% of patients and constitutes 60% offocal CNS mass lesions in HIV patients

Patients with toxoplasma encephalitis present with fever, headache and seizures.The patients may develop hemiparesis, ataxia and psychomotor retardation HIVpatients with toxoplasma encephalitis will have detectable serum antitoxoplasmaIgG in 90-100% of patients Antitoxoplasma IgM probably has little value in HIVpatients Cerebrospinal fluid PCR for toxoplasma is specific but not sensitive CTscan reveals iso- or hyperdense lesions in the hemispheric gray-white junction, whitematter or basal ganglia and 90% of lesions enhance as a ring or nodule (Fig 12.4)

If a single lesion is seen on MRI the likelihood of toxoplasma decreases to 34% andthat of primary CNS lymphoma increases to 56% On SPECT scan there is in-creased focal uptake in lymphoma and no uptake in toxoplasma and tuberculoma.Definite diagnosis of toxoplasma requires brain biopsy; however, a presumptive di-agnosis can be made on the basis of therapeutic improvement following py-rimethamine (100 mg po load, 75-100 mg four times daily and sulfadiazine 1.5-2 gqid) or pyramethamine and clindamycin (600-900 mg po qid) The clinical im-provement occurs in one to two weeks and radiological improvement occurs in two

to three weeks The primary treatment is continued for at least six weeks followed bychronic suppressive therapy for life The suppressive therapy includes pyramethamine(20-50 mg po qid) and sulfadiazine (1 gm po tid) or clindamycin (300-400 mg poqid) and folinic acid (10-50 mg po qid) Clarithromycin and atovaquone have alsobeen tried In 50-70% of patients there are dose-limiting side effects

Cytomegalovirus (CMV) Encephalitis

With the advent of highly effective antiretroviral therapy, the incidence of CMVinfection has declined drastically in the developed countries but may be prevalent indeveloping countries The CMV infection may be acquired through oral and respi-ratory secretion and contact with excreta, blood, semen and breast milk About80% of adults have antibodies against CMV, which is a member of the herpes virusgroup and may lie dormant in the CNS The hallmark of CNS infection is a largecytomegalic (25-30 µm) cell containing a large central basophilic intranuclear in-clusion body looking like an owl’s eye as it is separated from the nuclear membrane

by a halo Autopsy studies reveal cytomegalic cells, discrete foci of parenchymalnecrosis, microglial membranes and ventriculoencephalitis

CMV encephalitis presents with features of encephalopathy, confusion, entation, apathy, psychomotor slowing and cranial nerve palsy Ventriculoencephalitisbegins with cognitive loss and apathy progressing within a few days or weeks to astate of withdrawn mutism and brainstem signs Retinitis may also be present MRIreveals enlarged ventricles, increased periventricular signal intensity on T2 or both.CSF reveals mononuclear pleocytosis with elevated proteins Culture of CSF forCMV is specific but insensitive Detection of DNA by PCR in CSF is specific andsensitive CMV infection may produce hyponatremia due to adrenalitis, which may

disori-be a clue to its diagnosis Treatment of CMV encephalitis includes a combination ofgancyclovir and foscarnet

Progressive Multifocal Leukoencephalopathy (PML)

PML is caused by the JC virus infection This virus is classified in the papovavirus family It is a ubiquitous virus that becomes reactivated from latency in thekidney PML may be the first presentation of HIV It is usually seen at CD4 countsless than 100/mm3 Symptoms can include limb weakness, cognitive dysfunction,visual loss, gait disturbance, lack of limb coordination, speech or language distur-bance and headache

CT scanning reveals hypodense white matter lesions without enhancement oredema MRI lesions show increased signal attenuation on T2 and decreased attenu-ation on T1.13 CSF examination may yield a few WBCs and a normal opening pres-sure JC virus PCR may be helpful in the diagnosis of PML since it has a sensitivityand specificity of 92%.14-16 In situ hybridization may be useful for confirmation ofPML Autopsy reveals demyelination and giant astrocytes that are pleomorphic andhave hyperchromatic nuclei Oligodendrocytes appear altered with enlarged nucleithat stain abnormally dense with hematoxylin These also may have ill-defined in-clusion bodies.16

Table 12.3 Central nervous system infection associated with HIV

Protozoa: Toxoplasma gondii, Trypanosoma cruzi, Acanthamoeba,

Pneumocystis carinii Bacteria: Mycobacterium tuberculosis hominis, Trypanosoma pallidum,

Mycobacterium avium complex, Listeria, Salmonella, coccus, nocardia, mixed pyogenic bacteria

pneumo-Fungi: Cryptococcus neoformans, candida, aspergillus, coccidioides,

histoplasma.

Virus: Cytomegalo, herpes, varicella, J.C, Epstein-Barr, HSV8

Patients may have increased survival and improvement clinically with aggressiveantiretroviral therapy Ara-C or alpha interferon may be of some use, although itsrole is still controversial Survival is poor with a mean of four months and maximum

of 30 months

Primary CNS Lymphoma

Lymphoma associated with HIV is largely B-cell lymphoma that may be related

to the Epstein-Barr virus Patients may present with symptoms of confusion, argy, memory loss, hemiparesis and speech and language disorders Seizures andcranial neuropathies are also seen Lesions of primary CNS lymphoma commonlyaffect the deep white matter and are seen in the periventricular region, in the corpuscallosum and the basal ganglia on CT scan and MRI.9-10 Lymphoma can cross thecorpus callosum This propensity to cross may be helpful in differentiating lym-phoma from infectious etiologies that usually do not cross Additionally, the CNSlymphoma seen in HIV has a higher rate of multicentricity and an increased rate ofspontaneous central necrosis compared to lymphoma in non-HIV patients PCR inthe CSF may detect Epstein-Barr virus DNA

leth-It may be difficult to distinguish the lesions of toxoplasma from those of phoma on clinical grounds and neuro-imaging alone.11 Hence, a therapeutic trial oftoxoplasma may be undertaken as described above

lym-The mainstay of the treatment of primary CNS lymphoma is whole brain tion Steroids can help to reduce the lesions Survival is generally poor

radia-Kaposi’s Sarcoma of the CNS

Kaposi’s sarcoma, though rare, can cause lesions which present as cranial pathies, polyradiculopathy or myelopathy secondary to epidural metastasis with cordcompression Kaposi’s sarcoma is seen as a homogeneously enhancing mass lesionwith mild edema

neuro-Stroke

Hemorrhagic stroke may occur due to decreased platelets, ruptured mycotic eurysm and bleeding into an intracranial malignancy Ischemic stroke may be seen

an-in the settan-ing of arteritis or endocarditis (bacterial or marantic) Patients with

tuber-Table 12.4 Peripheral blood CD4 count and CNS infections

culosis can get a vasculitis that may cause basal ganglia infarcts This is due to volvement of perforating arteries as these pass through infected basal cisterns.12 Strokesare also seen with VZV (varicella zoster virus), fungal and bacterial infections (mu-cormycosis, aspergillosis, tubercular, syphilitic) Hypercoagulable states such as dis-seminated intravascular coagulopathy (DIC) and venous thrombosis due todehydration can also cause stroke It is unclear if there is an association betweenAIDS and stroke since intravenous drug addiction is a confounding variable in thispopulation Treatment of stroke and prevention of further events involves treatment

in-of the underlying causes i.e., infectious versus hypercoaguable states Rehabilitationtherapy similar to regular stroke is advised

Fig 12.4 Gadolinium enhanced cranial MRI on T 1 sequence in axial section showing ring ehancing lesions in basal ganglia and periventricular area in an AIDS patient with toxoplasma infection (courtesy of U K Misra).

HIV Infection in Children

The prevalence of infection in children is highest in the tropics where the tion is transmitted heterosexually In 1994, 8% of AIDS patients in Uganda werebelow 12 years of age and 95% of them acquired infection from their mothers Themajority of these children became symptomatic before their first birthdays and morethan 60% died before their second birthdays Progressive encephalopathy is themost common manifestation of HIV infection in children manifesting with devel-opmental delay in motor and intellectual abilities, weakness and pyramidal signs.Children may have repeated bacterial infection, dementia, microcephaly and CNSopportunistic infection CT and MRI reveal generalized brain atrophy and nonspe-cific T2 hyperintensity Antiretroviral therapy is the mainstay of the treatment alongwith treatment of coexisting infections.17

infec-Summary

HIV infection is a rapidly spreading pandemic Approximately 43 million peopleare infected with HIV worldwide and numbers are rapidly increasing Neurologicalmanifestations of HIV are well recognized HIV affects all parts of the neuraxisincluding the central and peripheral nervous systems, meninges and the muscles.The central nervous system can be affected directly by HIV, i.e., ADC, PML andother opportunistic infections including bacterial, viral and fungal In addition, pri-mary CNS lymphoma is also common in HIV The pathogenesis of the many neu-rological syndromes associated with HIV is not well delineated The diagnosis isdependent upon clinical presentation, blood tests, cerebrospinal fluid analysis,neuro-imaging studies and pathological studies of infected tissues The treatmentincludes anti-retroviral agents as well as individual therapies customized to treat theindividual opportunistic infections and antitumor treatment in appropriate neo-plastic conditions Major emphasis must be on prevention of HIV particularly inunderdeveloped countries In spite of recent advances in the neurological manifesta-tion of HIV, there is a need for further basic, clinical, epidemiological and therapeu-tic research to eliminate this rapidly progressive pandemic

References

1 Snider W, Simpson D, and Nielson S et al Neurological complications of acquiredimmune deficiency syndrome: Analysis of 50 patients Ann Neurol 1983;14:403-418

2 Dal Pan GJ and McArthur JC Neuroepidemiology of HIV infection NeurologicClinics 1996; 14:359-82

3 Piot P, Tezzo R The epidemiology of HIV and other sexually transmitted tions in the developing world Scand J Infect Dis (Suppl) 1990; 69:89-97

infec-4 Miller RF; Lucas SB; Hall-Craggs MA et al Comparison of magnetic resonanceimaging with neuropathological findings in the diagnosis of HIV and CMV asso-ciated CNS disease in AIDS J Neurol Neurosurg Psych 1997; 62(4):346-51

5 Price R, Brew B The AIDS dementia complex J Infect Disease 1988;158:1079-1083

6 Navia B, Jordan B, Price R The AIDS dementia complex I Clinical Features.Ann Neurol 1986; 19:517-524

7 Keating JM et al Evidence of brain methyl transferase inhibition and early braininvolvement in HIV positive patients Lancet 1991; 337:935-939

8 Brew BJ, Bhalla RB, Paul M et al Cerebrospinal fluid β microglobulin in patientswith AIDS dementia complex: An expanded series including response to Zidovudinetreatment AIDS 1992; 6:461-465

9 Santosh CG, Bell JE, Best JJ Spinal tract pathology in AIDS: Postmortem MRIcorrelation with neuropathology Neuroradiology 1995; 37(2):134-138

10 Thurnher MM, Thurnher SA, Schindler E CNS involvement in AIDS: Spectrum

of CT and MR findings European Radiology, 1997; 7(7):1091-1097

11 Loberboym M, Estok L, Machac J et al Rapid Differential Diagnosis of CerebralToxoplasmosis and Primary CNS lymphoma by Thallium –201 SPECT J NuclMed 1996; 37:1150-1153

12 Pinto A AIDS and cerebrovascular disease Stroke 1996; 27:538-543

13 Provenzale, JM and Jinkins JR Brain and spine imaging findings in AIDS tients Radiologic Clinics of North America 1997; 35:1127-65

pa-14 McGuire D, Barhite S, Hollander H et al JC virus DNA in cerebrospinal fluid ofHIV patients: Predictive value for PML Ann Neurolog 1995; 37:395-399

15 Price RW Neurological complications of HIV infection Lancet 1996; 348:445-52

16 Stoner GL, Agostini HT, Ryschkewitsch CF et al Detection of JC virus in twoAfrican cases of progressive multifocal leukoencephalopathy including identifica-tion of JCV type 3 in a Gambian IDS patient J Med Microbiolog 1998;47(8):733-742

17 Katabira ET HIV infection in the tropics In: Chopra JS, Sawhaney IMS eds.Neurology in Tropics New Delhi: Bichurchill Livingstone, 1999:127-139

CHAPTER 13

Tropical Neurology, edited by U K Misra, J Kalita and R A Shakir.

©2003 Landes Bioscience

Parainfectious Demyelinating Diseases

of the Nervous System

J Kalita and U K Misra

There is a wide spectrum of demyelinating diseases of the cerebral and eral nervous systems which are temporally related to infection These diseases arenot due to direct injury by the organism as the neurological signs appear late in thecourse or weeks after recovery and the virus cannot be isolated from the neuraltissues despite presence of inflammation and demyelination on histopathology Thepost-infectious demyelinating syndromes are usually associated with virus-like ill-nesses but can also occur following immunization, bacterial infection, surgery andpyretotherapy The spectrum of parainfectious demyelinating syndromes is wideand includes the following disorders: 1) acute disseminated encephalomyelitis; 2)acute hemorrhagic leukoencephalitis; 3) acute transverse myelitis; 4) optic neuritis;5) cerebellitis; 6) Guillain Barre syndrome (GB Syndrome); and 7) brachial andlumbosacral plexopathy

periph-Pathogenesis

Parainfectious demyelinating disorders bear a striking resemblance to mental autoimmune encephalomyelitis The latter is an autoimmune response tothe myelin basic protein and the proteolipid protein of the central nervous system(CNS) Cellular and humoral immune responses to myelin proteins occur, but thedisease can be passively transferred only with sensitized lymphocytes in transgenicmice who are devoid of CD8 B cells and have only mature CD4 T cells This experi-mental autoimmune encephalomyelitis suggests that antibodies are not critical forautoimmune encephalomyelitis A number of mechanisms have been proposed toexplain parainfectious demyelination: 1) direct viral effect; 2) virus induced im-mune mediated reaction; and 3) viral disruption of regulatory mechanisms of theimmune system

experi-Direct Viral Effect

Demyelination due to direct viral effect may be attributed to virus infection ofoligodendrocytes or Schwann cells This results in demyelination through cell lysis

or alteration in cell metabolism of the virus or viral product which may destroy themyelin membrane Few viruses such as measles, mumps, influenza and varicellacontain a fusion protein in their envelope Fusion protein can dramatically alter themembranes, even of cells not susceptible to infection or after the virus has beeninactivated by ultraviolet rays which may result in demyelinating changes Myelinbasic protein is an excellent substrate for protein kinase in the vaccine’s virus core.The release of this viral enzyme by a neighboring cell could have a profound effect

on myelin structure and function

Virus-Induced Immune-Mediated Reaction

In some viral infections, virus-specified polypeptides are introduced into theplasma membrane of the host cells Antibodies or cell-mediated immune reactionsagainst the viral antigen may destroy the host cell If the host cell happens to be anoligodendrocyte or Schwann cell (myelin supporting cells), this may result in demy-elination An alternative mechanism could be by exposing the sequestrated myelinantigen into the circulation following viral infection of myelin supporting cells.This results in an autoimmune response Molecular mimicry has also been sug-gested to explain virus-induced immune-mediated demyelination If virus polypep-tides share common antigenic determinants with central or peripheral nerve myelin,even a distant viral infection may trigger an autoimmune response against myelin.Molecular mimicry has been sought in the gene bank by looking for viral proteinsequences resembling the encephalitogenic sequence in the myelin basic protein.Tertiary structure and sequence alignment may lead to molecular mimicry such as asingle T cell receptor can recognize distinct but structurally related peptides fromdifferent pathogens Therefore, an encephalitogenic sequence of myelin protein might

be mimicked by peptides of a variety of viruses, a phenomenon which can explainhow diverse viral agents can induce demyelinating encephalomyelitis or polyneuri-tis

Parainfectious demyelination may also be due to an innocent bystander effect.During the inflammatory response evoked by a delayed hypersensitivity reaction,activated lymphocytes in macrophages release proteases or cytokines that can dis-rupt myelin, e.g., intracerebral inoculation of tuberculin-purified protein to a tu-berculin-sensitized guinea pig results in demyelination accompanied by inflammatoryresponse at the site of inoculation Similarly an immune reaction against a viralantigen in the vicinity of central or peripheral myelin can result in demyelinationwithout concomitant infection of myelin-supporting cells

Viral Disruption of Regulatory Mechanism of the Immune System

The phenomenon of self-tolerance was thought to result from deletion of thepotential “self ” reactive clones of lymphocytes at an early age Tolerance, however, is

an active process in which autoimmune reactions are suppressed by regulatory nisms of the immune system Infections may precipitate autoimmune disease byperturbating immunoregulatory mechanisms resulting in immune-mediatedparainfectious demyelination

mecha-Several mechanisms have been postulated for parainfectious demyelination Anantecedent viral infection could increase the vulnerability of nervous tissue to attackfrom a previously persistent subclinical autoimmune process Alternatively, viral in-fection of the myelin sheath or the myelin supporting cell could alter the pattern ofmyelin breakdown This can result in a disturbance of balance to trigger the autoim-mune process The most attractive hypothesis of parainfectious demyelination isthat the virus directly acts on T cell subsets, receptors disturbing the balance thatnormally prevents a symptomatic autoimmune reaction Measles and the Epstein-Barr virus, which are the commonest viruses related to acute disseminated encepha-lomyelitis and Guillain-Barre syndrome, respectively, alter T cell activity duringprimary infection

Acute Disseminated Encephalomyelitis

Acute disseminated encephalomyelitis (ADEM) is a frequent monophasic plication characterized by rapid onset of neurologic signs and symptoms followingviral exanthem in infants and young children ADEM occurs in 1 in 1,000 measlesinfections with a mortality rate as high as 25% and neurologic sequelae in 25-40%

com-of survivors.1 On the other hand, the incidence of ADEM following varicella zosterand rubella infections are 1:10,000 and 1: 20,000, respectively, with lower occur-rence of neurologic sequelae than measles In developed countries immunizationprograms have reduced the incidence of ADEM following measles; however, in Bra-zil, 20,000 cases of ADEM following measles have been reported in 1997.2 In thetropical countries, because of poor vaccination coverage, ADEM continues to be acommon health problem The important pathogens associated with ADEM includemeasles, herpes simplex virus, HIV, human herpes virus, mumps, influenza, Epstein-Barr and coxsackie B virus The frequency and severity of ADEM following these

viral infections is highly variable ADEM has also been reported to follow plasma pneumoniae and Legionella cincinnatiensis.1

Myco-Post-Immunization Encephalomyelitis

Post-immunization encephalomyelitis in most commonly associated with measles,mumps and rubella vaccinations The reported incidence of ADEM following measlesvaccination is 1-2 per million vaccination which is 20 times lower than that ofmeasles infection.3 Cases of ADEM have also been reported following semple anti-rabies and Japanese encephalitis vaccine The inciting factor in vaccination is notnecessarily the viral component, rather it is the CNS tissue contaminating the vac-cine Fortunately the vaccines are no longer prepared from in vivo infected CNStissue

Post-Organ Transplantation ADEM

Following organ transplantation, two cases of ADEM have been recently ported In one of them, Epstein-Barr virus was implicated Transplant patients may

re-be at an increased risk of viral infection or reactivation of latent virus due to term use of immunosuppresive therapy The risk of infection may also be increaseddue to transfer of infection from the organ donor to the recipient In a transplantpatient, however, the MRI changes similar to ADEM may well be due to a number

long-of drugs such as methotrexate, cyclophosphamide and cyclosporin Currently, ever, it is not clear if the incidence of ADEM in organ transplant patients is higherthan in the general population and further experience is necessary

how-Clinical Features

ADEM occurs most frequently in infants and young children A close temporalrelationship between infection or immunization with the onset of neurologic symp-toms and the presence of an exanthem may facilitate the diagnosis The clinicalpicture of classic ADEM is variable and clinical manifestations of this syndrome aresimilarly unrelated to triggering events The neurological symptoms usually beginone to three weeks after infection so that symptoms and signs of the triggeringinfection have generally improved In cases of exanthematous infections such asmeasles, the neurological symptoms appear as early as two to seven days after theappearance of the rash The neurological symptoms may, on rare occasion, precede

or accompany the rash Systemic manifestations, including fever, myalgia,

ache, nausea and vomiting, often precede neurologic symptoms of ADEM Theneurologic signs and symptoms include paresthesiae, pain, motor weakness, spastic-ity, lack of coordination, dysarthria and dysphagia Seizure may occur in severe cases,especially following measles in about 50% of patients Disseminated lesions canlead to stupor, coma and respiratory failure Optic neuritis is usually bilateral andtransverse myelitis usually complete

Pathology

Autopsy of a patient dying in the acute phase of ADEM reveals a swollen brainwith engorged veins in the white matter Microscopically there is characteristic perivas-cular edema with cellular infiltration The infiltrating cells are usually lymphocytesand macrophages, occasionally plasma cells and rarely granulocytes Macrophagesare frequently found to have ingested lipids A proliferation of endothelial cells and

a varying degree of demyelination with relative sparing of the axons are seen nohistochemical staining for various myelin antigens shows a similar pattern of myelinloss in the lesions in ADEM and experimental allergic encephalitis

Immu-Pathophysiology

Results of animal studies indicate both an infectious mechanism and a ary autoimmune response contributing to CNS demyelination in ADEM The ini-tial injury caused by an infectious agent may be followed by a secondary autoimmuneresponse It has been postulated that a common antigen shared by the infectiousagent or a vaccine and a myelin epitope can trigger an autoimmune response which

second-is known as molecular mimicry T cell-mediated autoimmune response to myelinautoantigen, such as myelin basic protein, proteolipid protein and myelinoligodandrocyte glycoprotein may result in ADEM after immunization in Freund’sadjuvent CD4+ and CD8+ T cells have been implicated in the secondary autoim-mune response, which has been observed following viral infections Mice with se-vere combined immune deficiency which are unable to mount an immune response

do not develop demyelination The role of B cells and antibodies to GMI and GDIahas been postulated It is possible that multiple immune mechanisms may contrib-ute to the effector phase in ADEM

Laboratory Investigations

There is no laboratory test or imaging procedure that unequivocally establishesthe diagnosis of ADEM An elevated ESR, proteinuria and acute phase reactantsmay be present Cerebrospinal fluid may reveal moderately elevated protein, lym-phocytic pleocytosis (below 200 cells/mm3) and normal sugar in 80% of patients.Occasionally patients have a higher count or a mixed polymorphonuclear lympho-cytic pattern during the initial days of illness

Other markers like oligoclonal band, IgG or myelin basic protein in CSF aresometimes detectable but are not specific Although viral proteins of herpes simplexvirus, human herpes virus VI, varicella zoster, HIV, enterovirus and EB virus havebeen detected in the CSF but their causal relationship is not clear Electroen-cephalography reveals symmetric slowing in the acute phase and spike and sharpwave discharges Occasionally spindle coma pattern and alternative pattern havebeen reported.4 Evoked potential abnormalities can also occur depending on the site

of involvement

Neuroimaging is extremely useful in the diagnosis of ADEM Both CT scan andMRI have been widely used in the diagnosis of ADEM, but MRI is superior to CT

scan A 5-14 day delay between the onset of physical signs and appearance of lesions

on imaging studies is common The typical CT findings in ADEM include hypodenselesions in the subcortical white matter, contrast enhancement of lesion and rarelyintracerebral calcification have also been reported.5 On MRI multiple hyperintenselesions on the T2 and PD sequence are seen in the subcortical white matter (Fig.13.1) These lesions are usually larger than those in multiple sclerosis (MS) and may

be symmetrical The lesions are of the same age, and no new lesions appear after theinitial clinical attack These features help in differentiating ADEM from multiplesclerosis PET study shows hypermetabolism in the affected area of the brain

Differential Diagnosis

Within the context of an acute encephalitogenic process following a viral tion or exanthem or both, atypical bacterial illness or vaccination accompanied byCSF pleocytosis and extensive and symmetric white matter changes on MRI, thediagnosis of ADEM is easy ADEM should be distinguished from acute viral en-cephalitis, multiple sclerosis (MS) and the paralytic form of rabies Acute viral en-cephalitis is very difficult to distinguish from the severe cerebral form of ADEM;however, presence of continued fever, seizures, signs of meningeal irritation andMRI may help in differentiating viral encephalitis from ADEM Further confirma-tion of encephalitis may be achieved by serology, polymerase chain reaction (PCR)and viral isolation In the absence of specific viral prodrome or history of immuniza-tion, it may be difficult to differentiate ADEM from acute MS Simultaneous onset

infec-of disseminated symptoms and signs indicating optic nerve, brain and spinal cordinvolvement are common in ADEM and rare in multiple sclerosis Similarly men-ingismus, seizures, drowsiness and coma are suggestive of ADEM The CSF exami-nation in MS patients may either be normal or have mild pleocytosis and devoid ofneutrophils Magnetic resonance imaging in ADEM reveals extensive and relativelysymmetric white matter abnormalities with diffuse gadolinium enhancement of allthe involved areas indicating active disease and a monophasic course In children,

MS occasionally has an explosive course It is better to classify these patients as anacute demyelinating disease incorporating this uncertainty The salient features dis-tinguishes MS and ADEM are summarized in Table 13.1

ADEM following antirabies vaccination needs to be differentiated from the dumb

or paralytic forms of rabies ADEM generally develops 8-21 days after rabies nation, which is somewhat shorter than the incubation period of rabies Prodromalfeatures, localized parasthesiae, spasms and hydrophobia are absent in ADEM There

vacci-is also a notable absence of virus and Negri bodies in the brains of the patients withADEM who die

Multiple white matter T2 hyperintense signal changes in ADEM should be ferentiated from those due to vasculitis, subcortical arteriosclerotic encephalopathy,neurosarcoidosis, progressive multifocal leukoencephalopathy, HIV encephalitis,subacute sclerosing panencephalitis, mitochondrial encephalopathy, leukodystrophies,leukoencephalopathies after chemotherapy and radiotherapy and osmotic myeli-nolysis

dif-Relapsing ADEM Versus dif-Relapsing Multiple Sclerosis

ADEM is a monophasic illness, but relapses have been reported occasionally.The affected children and young adults develop clinical symptoms consistent withADEM and most of them have a history of infection or vaccination preceding the

Fig 13.1 Cranial MRI, T2 sequence, axial section showing rounded hyperintense signal changes in cerebral white matter in a patient with acute disseminated encephalomyeli- tis.

illness In these patients the results of CT and MRI are also consistent with ADEM,but the subsequent relapses are indistinguishable from relapsing remitting MS It isconceivable that the underlying pathogenic mechanism of these two disorders may

be similar The distinction between ADEM and MS sometimes can be difficultbecause encephalopathy, bilateral optic neuritis and complete transverse myelitishave also been reported in the fulminant form of MS The following criteria, how-ever, may be helpful in differentiating relapsing ADEM from MS If the relapses areassociated with new symptoms different from the initial manifestations, it favors the

relapsing remitting type of MS The appearance of new lesions or temporal tion in the evolution of white matter lesions supports multiple sclerosis

separa-Course and Prognosis

In most patients, ADEM is monophasic lasting for two to four weeks althoughrecurrent attacks have been reported occasionally Recovery can begin within days,with complete resolution depending on the severity within a few days, but moreoften over weeks or months The prognosis of ADEM varies widely and may berelated to the triggering event and to the clinical syndrome Cerebellar ataxia inchildren in association with varicella is benign with essentially no death and rarelong-term sequelae Mortality rates of 10-40% are reported with vaccinia triggeredADEM and 24% with measles triggered ADEM; however, it may be followed bysequelae in 90% of the survivors The sequelae following ADEM include persistentseizures, behavioral and learning disorders, hemiparesis, paraparesis or quadriparesis,intellectual deterioration and blindness Rapid onset of severe and extensive deficitsare the most important determinants of poor prognosis

Treatment

Treatment is targeted to suppress a presumed aberrant immune response to aninfectious agent or vaccination The use of corticosteroids to reduce inflammation,migration of cells and leakage of serum protein across the blood brain barrier seemstheoretically sound, but there are no controlled studies to show the benefits of cor-ticosteroids in ADEM High dose methyl prednisolone (500-1000 mg) IV for threedays followed by oral prednisolone tapered over three weeks has been recommended.The dose should be reduced proportionately in children In uncontrolled studiesACTH, intravenous immunoglobulin (IVIg) and plasmapheresis have also shownsome benefits Unfortunately, it is difficult to evaluate the potential benefit of thesetherapies, as only case reports and series with small numbers of patients are avail-able There is no specific therapy for ADEM The symptomatic treatment includescontrol of fever, maintenance of vital functions, nutrition, prevention of decubiti,contracture, aspiration, venous thrombosis, and control of seizures Treatment ofcerebral edema is by osmotic agents, hyperventilation and corticosteroids

Acute Hemorrhagic Leukoencephalitis

Acute hemorrhagic leukoencephalitis (AHLE) is a rare, devastating, hyperacute,demyelinating disorder that may or may not represent a distinct syndrome and isregarded as a severe form of ADEM, although some consider it a distinct entitybecause of its clinical features, pathologic changes and association with different

Table 13.1 Distinguishing features of acute disseminated encephalomyelitis

from multiple sclerosis

1 Monophasic

2 Common in children

3 More rapid and complete recovery

4 Absence of oligoclonal band in CSF

5 Presence of fever, headache meningismus, altered sensorium, bilateral optic

neuritis, areflexia, shooting limb pains

etiologic agents Similar to ADEM, acute hemorrhagic leukoencephalitis occurs 1-20days after a virus-like infection The onset is abrupt, manifesting with fever, rapiddeterioration of consciousness, seizures and focal neurologic deficits The disease ismore fulminant and there are features of raised intracranial tension Occasionallythe disease may be localized to the posterior fossa AHLE is rarely associated withvaricella and measles and is more commonly associated with the influenza A virusinfection In an autopsy study of 30 patients fulfilling the histological criteria ofADEM, 17 were following measles, four rubella, six mumps, two varicella and onevaccinia On the other hand, out of eight patients with AHLE, five followed upperrespiratory tract infection and three did not have any antecedent illness The spectra

of precipitating factors in ADEM and AHLE are different Cerebrospinal fluid showspleocytosis with polymorphonuclear and red blood cells There is peripheral bloodleukocytosis, elevated ESR and proteinuria

Pathologically, ADEM and AHLE appear to represent a gradient of severity InAHLE, the brain is swollen with punctate hemorrhages and even large ring-likehemorrhagic lesions Microscopic examination reveals fibrinoid necrosis andperivenous demyelination associated with infiltration of the vessels with neutrophilsand occasionally eosinophils There is exudation of serum protein including fibrin,along with red blood cells and granulocytes The ring hemorrhages are associatedwith venous thrombosis

The differential diagnosis of AHLE includes viral encephalitis, acute bacterialcerebritis, venous thrombosis and multiple embolic infarctions The prognosis isgenerally poor and death occurs within two to four days of illness Treatment issimilar to AEDM

Localized Post-Infectious Demyelinating Syndromes

Optic Neuritis

Optic neuritis is an optic neuropathy caused by any process that results in flammation, infection or demyelination of the optic nerve Optic neuritis usuallymanifests in young adults with unilateral orbital pain and progressive loss of vision

in-It is twice as common in females with an annual incidence of 3.5/100,000 tion Initially the patient complains of visual loss, central and paracentral scotoma,diminution of vision and color desaturation, loss of depth perception and contrastdiscrimination Isolated optic neuritis may be a manifestation of MS in 20-80%patients Some cases of isolated optic neuritis probably represent forme fruste ofADEM, which are encountered after exanthematous illness in childhood Post-in-fectious optic neuritis has been reported after measles, rubella, mumps, cytomegalo,Epstein-Barr, HIV and varicella zoster virus infections Most patients with post-infectious optic neuritis have bilateral optic nerve involvement, in contrast to MSwhere it is usually unilateral Additional neurological symptoms may occur in aminority of patients Young age of onset also suggests that these episodes are notinitial manifestations of MS Evaluation of these patients should include both neu-rological and ophthalmological examinations including measurement of relative af-ferent pupillary defect, color vision, visual field and visual evoked potentials Visualevoked potential reveals prolongation of P100 latency Cranial CT scan is usuallynormal and MRI of the optic nerve may reveal hyperintense signal changes on T2.The prognosis is good except in varicella zoster Optic neuritis following varicella

A and B, polio, Epstein-Barr and herpes simplex virus have been implicated ebellar involvement is particularly prominent in ADEM following varicella infec-tion Cerebellar ataxia has been reported after measles, rubella and mumps It hasalso been reported following several bacterial and parasitic infections such as myco-

Cer-plasma pneumoniae, legionella, toxoCer-plasma, typhoid fever, tick paralysis, Borellia burgdorferi, cysticercosis and Plasmodium falciparum Cerebrospinal fluid may re-

veal mild pleocytosis There is no specific treatment Recovery is usually completebut may take up to six months

Acute Transverse Myelitis

Acute transverse myelitis (ATM) is an acute or subacute spinal cord dysfunctioncharacterized by paraplegia, horizontal level of sensory impairment and sphincterdysfunction in which secondary causes such as compressive lesions, tuberculosis,syphilis, arteriovenous malformation, trauma and malignant infiltration have beenexcluded The disease does not progress beyond four weeks.6 A preceding viral ill-ness is reported in 37% of patients Acute transverse myelitis is a disease of adultsand children; it is rare under the age of four years The peak incidence is in the mid-teens and around 40 years of age The seasonal and gender variations have beennoted The incidence of ATM has been reported to range between 1 and 5 million.Acute transverse myelitis has been reported following smallpox, measles, mumps,influenza, echo, herpes, Epstein-Barr virus infection and the rabies and smallpoxvaccinations Acute transverse myelitis has also been reported following bacterialand parasitic infections, such as scarlet fever, pertussis, mycoplasma, pneumococcalpneumonia and schistosomiasis The CNS involvement in measles and smallpox isassociated with encephalitis in 97% of patients and in only 3-4% it is restricted tothe spinal cord Acute transverse myelitis manifests usually after one week of theappearance of a rash It may accompany or precede the rash Following vaccination,ATM develops within 8-21 days On rare accassion vigorous physical activity hasbeen reported to precipitate ATM In 40-60% of patients there is no clear-cut his-tory of preceding events or illness It may be a remote affect of cancer Myelitisrepresenting the first episode of MS has been investigated in several long-termfollowup studies Fewer than 6% of cases with ATM turn out to be MS

Pathophysiology

The pathologic similarity between encephalomyelitis following exanthematousillness and vaccination has been suggested Either a direct viral attack on the ner-

vous system or an activation of a latent virus may be responsible In case of varicella,infection, ATM is caused by either direct invasion of the spinal cord by virus or byinflammation and localized vasculitis Mumps virus most likely causes ATM bydirect invasion, whereas Epstein-Barr and mycoplasma probably are carried throughindirect inflammation It is now generally believed that an immunologic responseagainst the CNS is the most likely pathogenic mechanism in the majority of thepatients with ATM This is supported by experimental allergic encephalomyelitis.The observation that animals with experimental allergic encephalomyelitis developneurologic illness in the setting of delayed skin hypersensitivity to the injected anti-gen strongly suggests a cell-mediated mechanism The role of antibodies is not clear.Spinal cord appears grossly normal but areas of frank swelling and softening may beappreciated Sections may not reveal an obvious lesion but sometimes there may befrank necrosis Histologically, there is patchy myelin breakdown in the white matteralong the distribution of the veins Subpial demyelination independent of veins mayalso be present along with slight meningeal exudation Perivenous lymphocytic in-filtration with occasional plasma cells is seen The lesions are more apparent in lat-eral white matter than in dorsal columns and are symmetrical The neurons may benormal but there may be extensive necrosis as well, especially in the parainfectiousgroup The most prominent changes are present in the dorsal region of the spinalcord but edema and demyelination may extend upwards, even up to the cervicalspinal cord and occasionally to the brainstem.7

Clinical Features

The clinical picture of ATM is fairly uniform despite the diversity of etiologies.The common presenting symptoms are weakness and sensory impairment in thelower limbs and dorsal radicular pain Sphincter disturbance is found in more then90% of patients The clinical picture usually develops rapidly Two-thirds of thepatients develop maximum deficit by 24 hours Less frequently, the evolution mayextend to four weeks Objective signs include muscle weakness, reflex alternation,horizontal sensory level and autonomic changes At the peak of neurologic impair-ment, all the patients show lower limb weakness, and 25% of them may show upperlimb weakness as well The cervical cord involvement is, however, more frequent if

Table 13.2 Differential diagnosis of acute transverse myelitis

1 Extramedullary (compressive)

Neoplastic—vertebral metastasis, meningioma Vascular—dural AV malformation

Infection—epidural abscess Vertebral abnormalities—congenital defects, disc protrusion.

2 Intramedullary

Neoplastic—Glioma, ependymoma Vascular—infarction, dissecting aneurysm, AV malformation Demyelinating—multiple sclerosis

Autoimmune disease—SLE, sarcoidosis, Sjogren’s syndrome Parainfections—herpes, cytomegalo, EB virus, Enterovirus, Mycoplasma, HTLV-1, HIV, syphilis

Post-vaccinial Substance abuse—IV opiate use

clinical, MRI and neurophysiological features are taken into account.8 Respiratoryinsufficiency may occur rarely in ATM patients with cervical cord involvement.Muscle weakness may vary from mild to severe Tendon reflexes are diminished orreduced in the paralyzed limbs during the acute stage and become exaggerated later.After a period of 10 days, wasting may become apparent in the patients with necro-tizing myelitis Loss of pain and temperature is more common, occurring in 90% ofpatients, compared to posterior column impairment which is present in 60% ofpatients The horizontal level of sensory loss is usually located in the mid- or highthoracic region, but occasionally it may be present in the cervical or lumbar region

A hyperesthetic band may mark the upper most segment Some patients strate a static segmental level, whereas others have an ascending pattern Fever mayaccompany the neurological deficit and up to one-third of patients may show neckrigidity On rare occasions, patients may have postural hypotension.9 The condi-tions that should be differentiated from ATM are summarized in Table 13.2

demon-Classical ATM is considered a monophasic illness, but a recurrent form of ATM

is a recognized entity now Primary recurrent ATM is rare and possibility of MS,systemic lupus erythematosus and arteriovenous malformation should be consid-ered Most patients with ATM have a symmetric sensory level which is less frequent

in MS The risk of developing MS after ATM is quite low in most studies Only 3%

of patients with ATM developed MS after 5 to 42 years of follow-up and most term studies have recorded rates of well below 25%

long-Investigations

Although no specific test of blood or CSF definitely diagnose ATM, a battery oflaboratory examinations may be necessary to identify underlying causes of the syn-drome or its complications These tests include blood count, serum chemistry, col-lagen profile, sedimentation rate, serum protein electrophoresis, HIV, HTLV-1, testfor tuberculosis and serum B12 levels Peripheral leukocytosis is present in one-third

of patients at the onset of ATM Cerebrospinal fluid analysis reveals mild to ate protein rise (100-500 mg/dl) and mononuclear pleocytosis (below 100/mm3).Occasionally CSF may be normal Partial myelographic block may be present in 5%

moder-of patients due to cord swelling MRI moder-of the spinal cord helps in excluding otherdisorders which can simulate ATM, such as intramedullary tumor, granuloma, vas-cular malformation and metastatic lesions In ATM, MRI reveals diffuse hyperintensesignal changes on T2 extending from a few segments to the whole of the spinal cord(Fig 13.2, 13.3) The MRI changes often extend above the sensory level by severalsegments On the axial section in the T2 sequence, a central hyperintense signalchange on T2 is seen which usually extends more than two-thirds of the cross sectionwith a central dot (Fig 13.4).10 In the T1 sequence, these changes are hypointense.Rarely, in necrotizing myelitis there may be hemorrhagic changes which gives rise tohyperintense signal changes on both T1 & T2 (Fig 13.5).9

Motor-evoked potentials to lower limbs are abnormal in 82% and tibial tosensory evoked potentials in 62% of patients with ATM.8 The changes are lessfrequent in upper limbs Concentric needle EMG has been used to document ante-rior horn cell involvement in ATM EMG reveals fibrillations and sharp waves in56% of patients with ATM, especially in lower limb muscles (unpublished observa-tion)

Fig 13.2 Spinal MRI, sagittal section, T2 sequences showing diffuse hyperintense signal changes in the cervical and thoracic spinal cord in a patient with acute transverse myelitis.

Fig 13.3 Spinal MRI, sagittal section, T 2 sequence showing hyperintense signal changes extending up to CV junction in a patient with acute transverse myelitis This patients had quadriplegia (with permission Misra UK, Kalita J, Kumar S J Neurol Sci 1996; 138:150-156.).

Treatment and Prognosis

Treatment of ATM has three aspects: 1) treatment of underlying cause such asacyclovir for herpes zoster, doxycycline for mycoplasma, etc.; 2) nonspecific immu-nosuppressive therapy; and 3) supportive care

There is no specific treatment for idiopathic ATM Prednisolone (1-1.5 mg/kg/day for 7-14 days), adrenocorticotrophic hormone (40-50 units daily for 7-10 days)

or a high dose of intravenous methyl prednisolone (500 mg I/V for 5 days) havebeen used without consistent benefits Supportive care of ATM includes prevention

of deep venous thrombosis by heparin 5000 units subcutaneously twice daily; vention of bed sores; amitriptylines or carbamazepine for pain; and monitoring ofrespiratory paralysis if present For retention of urine, catheter may be placed ini-tially but later, clean intermittent self-catheterization should be tried For manage-ment of constipation, bulking agents and suppositories may be used A rehabilitationprogram should also be instituted

pre-Recovery begins within 2-12 weeks of illness and continues for up to two years

If there are no signs of improvement for three months, it predicts a poor prognosis

In general, one-third of patients have good recovery with no or minimal sensorymotor deficit; one-third have fair recovery with significant sensory motor and sphinc-ter disturbance; and one third show no recovery About 5% of patients die due torespiratory failure The poor prognostic predictors of ATM include rapidity of on-

Fig 13.4 Spinal MRI, axial section, T2 sequence showing hyperintense signal change in the central portion of the spinal cord (central dot sign), in a patient with acute transverse myelitis.

Fig 13.5 Spinal MRI, sagittal section, T 1 sequence showing hyperintense signal changes

in the dorsal spinal cord in a patient with acute transverse myelitis suggesting rhagic lesions This patient had quadriplegia with postural hypotension (with permis- sion from Kalita J, Misra UK Post grad Med J 1996; 72:180-182)

set, dorsal pain, complete paraplegia, extensive signal changes on MRI, evidence ofdenervation on EMG and unrecordable motor-evoked potentials, especially on spi-nal stimulation.8,10 In a recent study on the prognosis of ATM, severity of weaknessand presence of denervation on EMG have been found to be most useful predictors

of the six month outcome In the early stage, motor and somatosensory evokedpotentials may be used instead of EMG for predicting the prognosis as the EMGchanges are apparent after two to three weeks only In our study of 31 patients, atthe end six months one patient died, 15 had a poor outcome and 15 had a goodoutcome.8

Guillain-Barre Syndrome

Guillain-Barre (GB) syndrome is an acute inflammatory demyelinatingpolyradiculoneuropathy The majority of these cases follow a virus-like illness Theannual incidence is one to two cases/100,000 population The latent period be-tween prodromal symptoms related to virus-like illnesses in the respiratory or gas-trointestinal systems is usually one to four weeks This duration is comparable to thelatent period for experimental autoimmune neuritis Although no specific etiologicagent is implicated in the majority of patients, diverse viruses have been sporadicallyincriminated on the basis of clinical diagnosis, antibody response or viral isolation

It is difficult to explain how different viruses with diverse antigenicity can take afinal common pathway leading to peripheral demyelination A list of viruses known

to trigger GB syndrome is shown in Table 13.3 The viruses most commonly related

to Guillain-Barre syndrome are Epstein-Barr, cytomegalovirus, HIV and hepatitis.Over the last decade GB syndrome has been recognized as a diverse disorder,including both demyelinating and axonal forms These distinctions are made on theFig 13.6 Schematic diagram showing various forms of Guillain-Barre syndrome.

basis of the clinical picture and electrodiagnostic testing which correlate with thepathology The recent types of GB syndrome include the classical GB syndrome, theaxonal form (acute motor axonal and acute motor sensory axonal neuropathy), theFisher form and other variants which have been depicted in the Figure 13.6

Pathogenesis and Pathology

Activated lymphocytes are found in peripheral blood and their numbers maycorrelate with disease severity Lymphocytes from both patients and experimentalanimals demyelinate the peripheral nerves in cultures of rat trigeminal ganglia Solublefactors are clearly involved in the immunological mechanisms as the patients withGuillain-Barre syndrome improve following plasmapheresis, and injection of thepatient’s sera to the sciatic nerve of normal rats produces demyelination IgM anti-bodies that bind to carbohydrates of peripheral nerves have been found in 90% ofpatients In the early stage of the disease, high resolution immunocytochemistryshows complement activation marker C3d and terminal complement complexneoantigen C5b-9 along the outer surface of Schwann cells Vesicular changes in theoutermost myelin lamellae are seen on complement positive fibers which are dem-onstrated prior to the invasion of macrophages.11 This suggests that antibodies arecross-reacting with epitopes on the Schwann cell membrane which may be crucial

in initiating the disease Pathological studies have shown perivenous accumulation

of mononuclear cells in patients throughout the length of the peripheral nerves Inthe early stage, the infiltrating cells are mainly CD4 but later macrophages predomi-nate.12 Segmental demyelination is found in the areas of infiltration and there isvesicular myelin degeneration and stripping of the myelin sheath by macrophages.Later, Schwann cells proliferate In some cases axonal degeneration predominates

Table 13.3 Viruses associated with Guillain Barre syndrome

CSF or nervous tissue

Infectious mononucleosis Epstein-Barr Hepatitis B

Hepatitis-A, B, non-A non-B Hepatitis B, A, C Coxsackie A1, 4,6

Influenza A & C Herpes simplex Mumps Measles Parainfluenza II, III Polio

Respiratory syncytial virus

Clinical Picture

Guillain-Barre syndrome has a subacute onset of areflexic motor paralysis with

or without sensory disturbance associated with albuminocytological dissociation ofCSF at the end of the first week of illness Fifty percent of patients develop maxi-mum deficit by two weeks and 90% within four weeks Progressive motor weaknessusually ascends from the legs to the arms but on rare occasion it may descend fromthe face to the arms to the legs Nearly half of the patients have bilateral facialweakness and only 5% develop external ophthalmoplegia A symmetric pattern ofweakness is usual Areflexia is not only present in the weak limb but also in the limbsthat are minimally affected Sensory symptoms are frequent at the onset but signsare usually not prominent More then 50% of patients have autonomic dysfunction

in the form of tachycardia, bradycardia, arrhythmia, postural hypotension, drosis and inappropriate secretion of antidiuretic hormone Transient involvement

anhy-of the bowel and the bladder occurs rarely The variants anhy-of GB syndrome are: 1)Fisher’s variant; 2) pure sensory; 3) autonomic; 4) axonal; and 5) relapsing type.Fisher’s variant is characterized by ataxia, areflexia and external ophthalmople-gia Weakness often appears later in the course

Laboratory Investigations

Cerebrospinal fluid examination in GB syndrome reveals raised proteins andpleocytosis which is generally up to 10/mm3; it may go up to 50/mm3 in patientswith HIV Nerve conduction studies in GB syndrome reveal distal latency prolonga-tion, conduction block, slowing of nerve conduction velocity and dispersion andprolongation of F wave latency The CSF and nerve conduction study may be nor-mal in the first week Most patients with GB syndrome are hospitalized and about30% require ventilatory assistance at some stage of their illness The prognosis isusually good; 85% of patients recover completely by six months and about 5% havepermanent disability The poor prognostic predictors are rapidity of onset, delay inrecovery, evidence of axonal changes and old age Mortality rates ranging between

10 and 20% have been reported but early ventilatory support has reduced the tality to 2-6% The cause of death in GB syndrome in 80% of patients is attributed

mor-to cardiovascular complication due mor-to aumor-tonomic disturbances Controlled studieshave not found benefit of corticosteroids Plasmapheresis has been advocated in theearly stage of disease especially within two weeks; two exchanges for mild and fourfor moderate and severe illness are recommended.13 Intravenous immunoglobulin0.4 gm/kg/day for five days is recommended as an alternative therapy with equalefficacy.14

Axonal GB Syndrome

Pure motor axonal variety of GB syndrome constitutes 10-20% of all the cases of

GB syndrome A large number of rural children in China and Mexico have beenreported to develop acute flaccid ascending symmetrical areflexic paralysis withoutany pleocytosis in the CSF during the summer Electrophysiologic and pathologicstudies have revealed acute axonal forms of neuropathy The age of onset, geographicdistribution, seasonal occurrence, epidemiologic and serologic evidences have im-

plicated Campylobacter jejuni as the major cause of diarrheal illness preceding the

axonal variety of GB syndrome which has been reported from China and sporadiccases worldwide.15 The pathological changes reveal predominant Wallerian degen-eration of nerves with minimal demyelination and inflammation Immunocytochem-

of sensory fibers in the acute axonal neuropathy could reflect an immune attack on

an epitope primarily located on the motor fibers; alternatively, the epitope may bepresent in all of the fibers, but quantitatively greater in motor fibers so that sensoryfiber involvement is seen in most severe cases These patients have a poorer progno-sis as compared to the usual GB syndrome.16

Brachial and Lumbosacral Plexopathy

Acute brachial neuropathy or neuralgic amyotrophy is a well-defined syndromecharacterized by acute onset of arm pain, mostly around the shoulder, followed after

a variable interval by flaccid paralysis of various shoulder girdle muscles It is usuallyunilateral but can be bilateral The annual incidence of neuralgic amyotrophy hasbeen reported to be 1.6/100,000 population with the age of onset ranging between

12 and 47 years and a female to male ratio of 1:1.75-10.5 Antecedent events occur

in 28-83% of patients which include infection (bacterial, parasitic, viral and specific), surgery and trauma to the areas remote from the shoulder girdle, immuni-zation such as tetanus, DPT, small pox, child birth and miscellaneous conditionsuch a lumbar puncture, radiologic contrast administration and allergy desensitiza-tion Specific illnesses such a systemic lupus erythematosus, temporal arteritis, poly-arteritis nodosa and Ehlers-Danlos syndrome may precipitate a syndrome resemblingneuralgic amyotrophy A non-traumatic brachial plexopathy has been reported withintravenous heroin addiction, but it tends to be painless and has a predilection forlower brachial plexus Typically, a few days may elapse after the antecedent eventbefore the onset of acute brachial neuropathy Pain sets in acutely which is constantand intense, described as a sharp stabbing, throbbing or aching in nature and isworse at night Usually it is localized to the shoulder, often with radiation to theneck and down the arm It is aggravated by movement of the arm and shoulder but,unlike cervical root pain, it is not aggravated by coughing, sneezing or neck move-ment Pain may be bilateral even with unilateral paralysis Pain persists from a fewhours up to three weeks, but occasionally may last much longer On rare occasionpain may be absent in otherwise typical cases Weakness is usually noted as painsubsides within one to two weeks The severity of weakness varies considerably andupper plexus muscles around the shoulder girdle are commonly affected Weaknessmay also be confined to a single nerve distribution or may affect several nerves Thelong thoracic nerve is most frequently involved, followed by the suprascapular, axil-lary and, rarely, the musculocutaneous, anterior interosseus and radial nerves Thedeltoid is affected in 31-100%, serratus anterior 17-74% and spinati in 51-91%.Sensory loss is found in 33-70% patients A numb patch over the outer aspect of theshoulder and along the radial nerve are the most common sensory abnormalities.Lack of sensory loss may be due to involvement of the motor nerve The deep ten-don reflexes are variable and may be absent or reduced in the affected muscles Theprecise location of the lesions is difficult to find because the muscles are inexplicablyspared or sensory or motor changes do not correspond Diaphragmatic palsy mayaccompany in 6% of patients Bilateral signs and symptoms may be present in 25-30%

non-of patients Recurrence non-of symptoms may be present in 1-5%