Neuroimmunology in Clinical Practice - part 5 potx

NICP_C05 04/05/2007 12:26PM Page 103 Acute disseminated encephalomyelitis Box 5.13 • • • • • 103 Etiological association of acute hemorrhagic leukoencephalitis Para-infectious (e.g Influenza A, RSV, mycoplasma, varicella, measles and other exanthematous illnesses) Postvaccination (especially Pasteur rabies vaccine; hepatitis B) Encephalitis (HSV, HHV6, VZV) Fungal cerebritis (e.g Scopulariopsis phaeohyphomycosis) Drug or toxin exposure (e.g intrathecal methotrexate) presence of red blood cells (Leake and Billman, 2002) Imaging studies disclose fairly symmetrically distributed hemorrhages in deep white matter, some of which may coalesce into large somewhat asymmetrical hemorrhagic areas Thalami, hypothalamus, brainstem, cerebellum, and spinal cord may also be involved, while cerebral cortex and basal ganglia tend to be spared Involved tissues may be quite edematous The disease is fulminant with death usually ensuing within hours to days A number of reports of favorable response to high doses of intravenous corticosteroids (Seales and Greer, 1991) and appropriate additional treatments of increased intracranial pressure suggest that AHLE may be treatable if recognized quickly Plasmapheresis and cyclophosphamide have also been employed with apparent effectiveness in a few cases Rapid and effective treatment requires recognition of the presence of AHLE, a diagnosis that has been confirmed in some instances by urgent brain biopsy, followed by successful treatment (McLeod, 2001) Craniectomy appears to have been beneficial in some cases with severe elevation of intracranial pressure Severe cases have become rarer due to the availability and increased safety of vaccines, permitting children to be effectively vaccinated against many illnesses associated with the possibility of AHLE However, small quantities of red blood cells (10–500 /mm3) that are often found in lumbar CSF of children with ADEM suggests the possibility that milder degrees of AHLE, falling below the resolution of scan techniques, continue to occur Moreover, it has been compellingly suggested that cerebral malaria is the result of a hyperergic host response with the production of AHLE (Toro and Roman, 1978) • • • • • • • Blood dyscrasias (e.g acute myeloid leukemia) Fat embolism Nutritional deficiencies Ulcerative colitis Acute rheumatic fever Membranoproliferative glomerulonephritis, acute tubular necrosis Asthma Concentric sclerosis, Balò type (CSBT; encephalitis periaxialis concentrica) This illness, which may be a peculiar hyperacute variant of MS, may in addition be influenced by genetic factors that may admix features of both MS and ADEM (Caracciolo et al., 2001; Itoyama et al., 1985; Kira et al., 1996; Moore et al., 1985; Sotgiu et al., 2001) The rarity of this illness appears to be on the order of Schilder disease and its etiological basis similarly uncertain Peak incidence is in the third decade of life, although cases may arise as early as the second and as late as the sixth decade The male to female ratio is about 1:2 CSBT appears to have higher incidence in Taiwan, Japan, or the Philippines (Tabira and Nishizawa, 1990; Tabira, 1994) Mild prodromal fever, malaise, and headache are noted in approximately half of CSBT cases, followed by behavioral withdrawal The acute behavioral change is associated with weakness and numbness, initially on one side of the body (face, limb, or trunk) that then worsens in extent and degree Development of pyramidal or cerebellar signs and deterioration of higher cortical and oropharyngeal functions ensue A Dévic syndrome phenotype is occasionally found (Currie et al., 1970) Generalized convulsions occur in approximately 25% of cases The clinical course may suggest ADEM, especially in younger individuals with this condition Blood and CSF tests reveal little information of diagnostic importance; mild CSF pleocytosis may be found (Tabira, 1994) Historically, diagnosis was ascertained in severe cases by postmortem or brain biopsy Pathological study of the concentric layers of greater or lesser degrees of demyelinative and remyelinative inflammation suggest similarities with the appearance of the NICP_C05 04/05/2007 12:26PM Page 104 104 ROBERT S RUST edge of MS plaques (Courville and Cooper, 1970; Moore et al., 1985; Yao et al., 1994) MRI scans have proven useful in identification of milder cases of CSBT Between 3–5 fairly symmetrical lesions 1.5–5 centimeters in diameter are typically found, more commonly in the deep cerebral (frontoparietal > temporal) or cerebellar white matter than in other rarer locations, such as spinal cord (Currie et al., 1970) During the early acute stage of CSBT gadolinium enhancement may clearly delineate alternating concentric zones of greater or lesser inflammation, quite distinct from what is seen in typical ADEM or MS In the late acute stage only a single ring of enhancement at the outer margin of lesions may be found more closely resembling MS (which the age at presentation usually suggests) or ADEM (which the febrile prodrome may suggest) The concentric rings may reappear during the ensuing subacute phase of illness (Caracciolo et al., 2001; Chen et al., 1999; Chen, 2001; Ghatak et al., 1989) MR spectroscopic abnormalities of CSBT resemble those found in MS plaques, although similar changes are found in other diseases, including mitochondrial cytopathies (Chen, 2001) In addition to ADEM and MS, tumor, vasculitis, or infection may resemble CSBT (Caracciolo et al., 2001) Caution is especially important where the pattern of alternating enhancement is less centrifugal and more irregular in arrangement Biopsy may sometimes prove misleading Reported CSBT cases, chiefly from the pre-MRI era, have generally proved fatal within 2–60 weeks Early deaths are due to herniation, late deaths to inanition and secondary infections (Courville and Cooper, 1970; Tabira, 1994) Milder cases identified by MRI and increased availability of supportive therapies have modestly improved the overall outlook for this condition Early provision of immunosuppressive treatments may ameliorate clinical and imaging abnormalities Some cases arising in fourth–sixth decades have longer survival and more prominent gliosis of demyelinated layers Optic neuritis (ON) Optic neuritis is considered in detail elsewhere in this volume In this section childhood ON and its relationship to ADEM and MS will briefly be reviewed ON may also occur in association with various inflammatory illnesses other than ADEM or MS (Kazarian and Gager, 1978; O’Halloran et al., 1998; Riedel et al., 1998) ON is rare prior to six years of age and more common from six years of age to puberty Prior to puberty it usually occurs in association with ADEM or NMO In approximately 70% of cases, acute visual loss occurs days to weeks after a nonspecific viral illness (especially measles, mumps, and varicella) or immunization (Kazarian and Gager, 1978; Kline et al., 1982; Purvin et al., 1988; Riikonen, 1989) After puberty, it may occur in isolation or in association with NMO or MS and the association with a prodromal illness is less common In isolated postpubertal cases the risk for subsequent diagnosis of MS is approximately 50% Visual loss of childhood ON may be preceded by headache (frontal or ocular), scintillating scotomata, or painful eye movements Visual loss may be unilateral or bilateral Three-quarters of prepubertal cases develop bilateral changes either simultaneously or sequentially, the changes in the second eye lagging behind the first by weeks to months Degree of visual loss is usually fairly symmetrical in bilateral cases, however, in a significant minority of cases it is asymmetrical (Riikonen et al., 1988) Initially the visual disturbance may be limited to visual blurring with progression over several days to partial to complete visual loss In cases with partial visual field loss there may be a particularly dense central scotoma Swelling of the optic nerve head (papillitis) is more common in children than it is in adults with ON, occurring in at least two-thirds of cases (Kriss et al., 1988; Parkin et al., 1984) Quite striking abnormalities, including fiber layer hemorrhages at the optic nerve margin, vascular tortuosity, or sheathing of veins, are readily observable on funduscopy in many cases (Riikonen et al., 1988) These changes may suggest papilledema, however, the visual loss of ON can, in most cases, readily be distinguished from that due to malignantly increased intracranial pressure (ICP) Increased ICP is usually associated with additional neurological signs (e.g sixth nerve palsy, meningismus) It manifests slower onset and as it usually provokes less profound degree of visual loss is less frequently associated with an afferent pupillary defect As in many cases of adult ON, childhood ON may occur without observable funduscopic changes, in which case the term retrobulbar ON is applied The diagnosis of ON is made on the basis of a combination of clinical and laboratory findings In subtle cases, diagnosis can be clinically supported by loss of red vision (“red desaturation”), or by loss of duration or variety of the “flight of colors” that are apprehended in a dark room immediately after 60 seconds of stimulation of a retina with bright light Greater NICP_C05 04/05/2007 12:26PM Page 105 Acute disseminated encephalomyelitis degrees of visual loss are signified by the presence of an afferent papillary defect (APD – loss of the reflexive constriction of the contralateral pupil when the retina of the affected eye is illuminated) Visual evoked responses (VER) are particularly useful where visual loss is mild enough to be uncertain ON results in increased latency of the positive component of this cortical response (Feinsod et al., 1975) Delayed VER may persist for several years in patients who have shown excellent clinical recovery (Aicardi, 1992) Abnormalities of other portions of the nervous system should be sought and if found a more general diagnosis (e.g ADEM, Dévic syndrome, Guillain– Barré syndrome (GBS), MS) should be applied on the basis of clinical features and history Positivity of the CSF immune profile studies noted above (excepting myelin basic protein) or of other studies such as CSF free kappa chains (Rudick et al., 1986; Riikonen et al., 1988a) favors the diagnosis of MS but does not exclude the diagnosis of ADEM MRI scanning of brain and brainstem with appropriate weighting (T1, T2, balanced, and with gadolinium administrations) and special orbital views is important MRI demonstrates swelling of the optic nerve in most cases; the extent of optic nerve enlargement may be alarming in some children who nevertheless experience good recovery MRI is the most important tool in excluding alternative diagnoses such as lesions compressing the optic nerve Disseminated T2 bright lesions may be found by MRI elsewhere in the brain in as many as 70% of patients (Riikonen et al., 1988), interpretation of such changes in children is difficult and may not indicate MS Where such abnormalities are at the gray–white junction and the patients are younger, ADEM is suggested Periventricular plaques (especially if perpendicular to the ventricular surface) are more suggestive of MS (Ormerod et al., 1986) SSPE, intoxications (e.g methanol), leukodystrophies, and stroke must occasionally be considered Malingering may be excluded on the basis of inconsistencies on examination or with VER testing Generally, recovery from idiopathic childhood ON is excellent, although the rate of recovery may be slow (Good et al., 1992) The most common residua include optic nerve atrophy and impairments of color and stereoscopic vision (Parkin et al., 1984; Purvin et al., 1988) Permanent severe visual loss is quite exceptional Bilateral presentation after an antecedent illness or immunization usually (although not always) implies good prognosis for visual recovery 105 (Parkin et al., 1984; Riikonen et al., 1988b; Good et al., 1992) Postpubertal ON is more likely to have residual deficits In adults, treatment with intravenous high-dose methylprednisolone of first bout of ON hastens recovery and may prolong the time to diagnostic recurrence of MS Oral prednisone provides no benefit and may heighten odds of early recurrence of a bout diagnostic of MS (Beck et al., 1992; Beck et al., 1993; Silberberg, 1993) These cases were chiefly first bouts of MS and the relevance of this data to children, many of whom not go on to develop MS, is unclear Recovery occurs with or without anti-inflammatory therapy in most children and there is little evidence that final recovery is favorably influenced by treatment High-dose intravenous treatment for 3–5 days in cases of quite profound optic nerve swelling may prevent ischemic injury and other childhood ON may manifest more rapid recovery with such treatment Limited data suggests treatment may reduce chances for ultimate diagnosis of MS ( Jacobs et al., 1994) ON may recur Various studies, following up for 2–18 years, have estimated a 0–60% risk for MS if a bout of ON occurs before 18 years of age (Kriss et al., 1988; Parkin et al., 1984; Riikonen et al., 1988) A more refined estimate suggests 15–30% overall risk (ON Study Group, 1997), chiefly sustained by those over 12 years of age, in whom there is about a 50% risk Poor or incomplete visual recovery, itself chiefly a postpubertal phenomenon, also implies a 50% risk for ultimate diagnosis of MS (Good et al., 1992) The presence of lesions consistent with MS plaques in typical locations (periventricular, forceps major and minor) on MRI increases the risk for subsequent diagnosis of CD-MS to at least 75–80% The presence of oligoclonal bands in the CSF also increases the risk for diagnosis of MS within five years, although not so decisively as the MRI features just noted Oligoclonality increases risk even where the MRI is normal (Cole et al., 1998) Risk of MS is high in unilateral ON (which is mostly postpubertal) and trivial in bilateral prepubertal cases (Parkin et al., 1984) In cases where ON is associated with ADEM, GBS, or Dévic syndrome, the prognosis should be determined on the basis of the more disseminated illness, but visual recovery is usually good Acute transverse myelitis (ATM) Various causes for acute childhood/adolescent myelopathy are listed in Box 5.14 The most common NICP_C05 04/05/2007 12:26PM Page 106 106 ROBERT S RUST Box 5.14 • • Causes of acute transverse myelitis Isolated ATM – Abscess* – Hemorrhage – Stroke (vascular malformation, compressive, embolic*) – Radiation – Tumor (spinal,* spinal root, meningeal, vascular, bone) – Trauma* More widespread neurological disease – Dévic syndrome (see below)*** – Encephalomyeloradiculoneuropathy*** – Multiple sclerosis*** – ADEM*** – Guillain–Barré syndrome – Neurosarcoidosis** causes are inflammatory, traumatic, or vascular In children, post-infectious/post-vaccination inflammatory myelitis is a particularly important category These cases are often a form of ADEM, including Lyme myelitis (Kerr and Ayetey, 2002; Rousseau et al., 1986; Tyler et al., 1986) Infections precede ATM by days to several weeks in 60% of cases (Paine and Byers, 1953) The additional history of blunt trauma to the spine is not infrequently recalled The cervical location is a common one as is thoracic Many more levels of the spine may be involved than is typical of MS In some instances the entire spine is involved as well as some of the brainstem In some instances the inflammatory sensitization involves both central and peripheral (e.g spinal root) myelin (Abramsky and Teitelbaum, 1977) The irreversible injury with myeloclasia that complicates severe ATM is likely to be vascular: due to the ischemia induced by cord swelling within the confined space of the spinal canal ATM that occurs in the first few years of life may be particularly malignant, but most cases occur in children more than five years of age (Aicardi, 1992; Berman et al., 1981) Pain and dysaesthesiae in the region of the developing ATM are the most common early symptoms Fever and meningismus may then follow Paraplegia, sensory loss, and sphincter dysfunction may develop slowly over days to many weeks or paroxysmally within several hours The rate of onset is often proportional to the intensity of the initial discomfort • – Tropical spastic paraparesis** (Link et al., 1989) In association with systemic disease – AIDS vascular myelopathy*,** (Rosenblum et al., 1989) – Chronic progressive (third stage) Lyme neuroborreliosis**,*** – Systemic lupus erythematosus** – Syphilis *Seldom if ever found in children; **Imaging changes may resemble ADEM or MS; ***May be manifestation of ADEM or MS Interferon beta-1b in the treatment of multiple sclerosis: final outcome of the randomized controlled trial The IFNB Multiple Sclerosis Study Group and The University of British Columbia MS/MRI Analysis Group, Neurobrucellosis Intense pain in neck presaging hyperacute cervical ATM is a medical emergency that may have a fatal outcome due to cardiorespiratory compromise In most instances bilateral flaccid areflexic paraparesis with a sensory level and sphincter dysfunction develop, followed in a few days by spastic weakness in the same distribution Superficial reflexes (abdominal, cremasteric, bulbocavernosus) are usually absent Partial spinal cord syndromes (e.g Brown–Sequard syndrome) or Dévic syndrome may be found Rarely ATM presents with the isolated complaint of urinary retention (Ropper and Poskanzer, 1978) ATM with febrile infectious prodrome and associated constitutional symptoms is more common in prepubertal patients and suggests ADEM ATM without these associated features is more common in adolescents and is suggestive of MS MS tends to provoke a less complete form of myelitis than ADEM The MRI of patients with MS-related myelitis typically demonstrates T2 bright signal abnormality of some, but not all, areas of the cord that are enriched with myelinated fibers The outlook for recovery may be poorer and that for severity of MS may be greater in adolescents that are found to have signal abnormality through many rather than few levels of the spinal cord Adolescent patients with purely spinal manifestations suggesting MS should be screened for tropical spastic paraparesis/HTLV-1 associated myelopathy (TSP/HAM), while men should be evaluated for adrenomyeloneuropathy (Walther and Cutler, 1997) NICP_C05 04/05/2007 12:26PM Page 107 Acute disseminated encephalomyelitis Some combination of history, examination, imaging studies, and CSF and serum tests discloses an etiological diagnosis (from among those listed in Box 5.14) for ATM in approximately two-thirds of the cases encountered in children and adolescents MS-associated ATM is almost entirely confined to postpubertal individuals, ADEM-related ATM to prepubertal individuals Imaging studies of brain and spinal cord are important in order to disclose distribution and in some instances cause of disease, as well as lesions or edema that require urgent therapy in order to prevent irreversible ischemic injury Unsuspected brain lesions may be found in MS, ADEM, neurosarcoidosis, and other diagnoses (Miller et al., 1987; Sanders et al., 1990) Myelography is sometimes helpful (Narciso et al., 2001) CSF pleocytosis is present in 25%, increased CSF protein in 50% of presumed ATM cases (Aicardi, 1992) No therapy, including corticosteroids, has been rigorously proven to be efficacious in the treatment of ATM Management is largely symptomatic, with particular attention to careful management of such associated problems as urinary retention and impaired breathing Pain and dysaesthesiae may be troublesome and vigorous attempts should be made to treat these symptoms, particularly where they interfere with sleep Some degree of recovery occurs in 80–90% of children, requiring weeks to months Approximately half of children with ATM will show excellent recovery; 10–20% develop cord necrosis and not recover Most of the remainder have variable residua (Ropper and Poskanzer, 1978; Berman et al., 1981) The most important prognostic factor is acuteness of onset; recovery is poor after hyperacute onset (Dunne et al., 1986) A very small number of children with cervical ATM die from cardiorespiratory arrest or upwards herniation Despite the lack of established efficacy, very high doses of anti-inflammatory agents may be tried in cases of progressive cervical ATM, particularly those with hyperacute and potentially lifethreatening presentation Ultimate diagnosis of MS is made in only about 10% of adults who experience ATM; the diagnosis of MS after isolated childhood ATM is probably even more exceptional (Aicardi, 1992) Neuromyelitis optica (NMO, Dévic syndrome) In children with NMO the signs of ATM and ON may develop simultaneously or in rapid succession Most prepubertal cases develop within days to weeks 107 after a viral illness or immunization The transverse myelitis is typically sudden and severe, producing paraplegia ON often develops in both eyes bilateral, onset in the second eye occurring days to months after the first Funduscopic changes of papillitis are usually, but not always, present The prodromal illness is less commonly discerned in postpubertal cases, the myelitis less complete, and there is a greater tendency for the ON to be unilateral More detailed description of this entity and recent advances in understanding of pathogenesis, classification, differential considerations and diagnostic testing are considered elsewhere in this volume There is no generally accepted therapy for DS However, very high doses of intravenous corticosteroids may be considered where optic nerve or spinal cord swelling is particularly alarming, in order not only to attenuate the inflammatory process, but also to close blood– brain barrier and prevent swelling that may lead to tissue ischemia Encephalomyeloradiculoneuropathy (Miller–Fisher/Bickerstaff encephalitis) Some cases of ADEM with prominent myelitis will have peripheral nerve signs, representing clinical overlap with GBS This overlap is particularly prominent in patients with AIDS Tumors with involvement of the cauda equina or nerve roots must also be considered The anti-Hu-associated paraneoplastic syndromes that should also be considered in adults have not yet been shown to occur in children (Dalmau et al., 1992) Acute necrotic encephalitis (ANE) The pathogenesis of this early childhood illness that has chiefly been reported in Japanese and Taiwanese (Mizuguchi et al., 1995; Voudris et al., 2001) remains obscure Although some type of inflammatory encephaloclasia is a likely explanation, it is unclear whether this might be due to a primary infectious process As with ADEM, there is a male predominance (boy to girl ratio = 2:1) Most cases arise between 6–24 months of age, although cases have occurred in children as old as five years The onset is typically marked by fever and rapid deterioration of mental status in association with convulsive seizures and brainstem signs Abnormalities of liver enzyme testing may be found MRI scans of severely affected children disclose symmetrical bright lesions on T2 weighting that NICP_C05 04/05/2007 12:26PM Page 108 108 ROBERT S RUST involve the thalami, hypothalamus, brainstem tegmentum, and cerebellum Bright signal may also be found in cerebral white matter Some of these abnormalities (particularly those representing edema) and clinical status may improve with high doses of intravenously administered corticosteroids Some particularly malignant cases appear to have favorably responded to heroical treatment with surgical decompression of intracranial pressure The gray matter lesions may become cavitary and death has occurred in approximately half of recognized cases This severe disease must be differentiated from those cases of presumed ADEM whose imaging manifestations may be confined to or emphasized in white matter and thalami The patients with these ADEM-related manifestations tend to be older (0.4– years of age) and their disease evolution is much less severe than is observed by the infants with ANE The outcome is favorable, with resolution of scan changes once recovery occurs (Cusmai et al., 1994; Marcu et al., 1979; Suwa et al., 1999; Tenembaum et al., 2002) It is not entirely clear whether some reports of milder cases of ANE from which infants recover without subsequent relapse are cases of mild ANE or of ADEM ANE must not be confused with some cases that fall within the ADEM/childhood MS/“recurrent ADEM” spectrum that manifest large pseudo-cavitary lesions of deep white matter sparing basal ganglia or thalamus, or with AHLE or Balò disease, all diseases for which high doses of intravenous corticosteroids may prove beneficial The differential diagnosis also includes tumor, infectious, metabolic, or vascular (e.g sinovenous thrombosis) diseases of brain Subacute-onset disseminated CNS illnesses that may be forms of ADEM Considerable recent interest has focused on the possibility that certain complex subacute-onset illnesses with extra pyramidal, psychiatric, and behavioral manifestations may represent post-infectious diseases that have mechanisms similar to ADEM or might respond to therapies advocated for ADEM and related illnesses The basis for such speculation derives in part from the strong evidence that one such illness, Sydenham chorea, is a post-infectious condition that is known to be provoked by certain strains of Group A β-hemolytic streptococci Recent studies have attempted to characterize another entity, termed pediatric autoimmune neuropsychiatric disorder (PANDAS) Attention has also been directed to the study of the neuropsychiatric disturbances that may develop in patients with rheumatic fever without associated chorea, observations that some believe will have pertinence to the development of isolated psychiatric disturbances (Mercandonte, 2000) or such controversial entities as “chronic fatigue syndrome.” During the past two decades, a number of cases of indolent psychiatric disturbances associated with “ADEM-like” MRI abnormalities have been reported, as has the gradual improvement of images and affect with corticosteroid treatment Investigators have suggested that these are examples of “subacute” limbic or disseminated encephalomyelitis ( Johnson et al., 1985) These cases have tended to have no clear association of deterioration with a preceding febrile illness or vaccination and CSF immune profile studies if obtained have been normal Meningoencephalitic encephalitis and other infections with possible ADEM-related complications The role that inflammatory dysregulation plays in the pathogenesis of CNS infectious conditions has received increasing scrutiny in the past decade and falls outside of the scope of this review The extent to which mechanisms closely resemble those of ADEM or MS, the role of genetics, and the pertinence of anti-inflammatory therapy for these conditions are as yet incompletely understood These conditions constitute part of the differential diagnosis of ADEM and MS, and may produce similar imaging or CSF abnormalities The presence of pial or cortical gadolinium enhancement on T1-weighted images is suggestive of encephalitis rather than ADEM The borderland between HSV2 encephalitis and ADEM is especially unclear when there are widespread lesions, some such cases responding very well to acyclovir treatment (Chu et al., 2002), some apparently benefiting from the addition of antiinflammatory therapy Acute or “relapsing” HSV2 encephalitis may be especially difficult to distinguish from ADEM (Chu et al., 2002) Some widespread HSV2 “recurrence” is a form of ADEM, responsive to corticosteroid treatment with a good outcome (Tulyapronchote and Rust, 1992) Chronic progressive Lyme encephalomyelitis or third-stage neuroborreliosis may also be a form of ADEM (Braune, 1991; Pavlovic et al., 1993; Reik et al., 1985) Japanese B, measles, and mumps encephalitides, cerebral malaria, and the CNS manifestations of Dengue all likely entail immuno NICP_C05 04/05/2007 12:26PM Page 109 109 Acute disseminated encephalomyelitis dysregulation that may involve ADEM-related mechanisms and may prove responsive to therapies aimed at this form of pathogenesis The presence of pial enhancement, which is not a finding in ADEM, suggests active meningoencephalitis Metazoal parasitic diseases of brain (e.g cysticercosis) may produce imaging changes that closely resemble ADEM, Box 5.15 I II although the pathogenic mechanisms of ADEM are probably not involved Summary Box 5.15 includes hypothetical criteria for various ADEM spectrum diagnoses in children Criteria for various suggested diagnostic groupings of ADEM family Tentative ADEM (T-ADEM) Preceding exogenous provocation (required) a Febrile, likely infectious illness or vaccination within 28 days b At least 12 hours afebrile improvement prior to ADEM-related deterioration Neurological deterioration: required a At least two separate clinical lesions, otherwise unexplained b At least three of the following: (1) Recurrence of fever, irritability, or lethargy at onset (2) Bilateral optic neuritis (3) MRI typical for ADEM (see text) (i) Cortical ribbon– subcortical white matter junction (ii) Indistinct margins (“smudge” appearance) (4) Focal or generalized EEG slowing (5) Elevated myelin basis protein with normal CSF immune profile (6) Clear improvement ≤24 hours after high-dose intravenous steroids Other relevant diagnoses, including MS, excluded by appropriate testing Probable ADEM (P-ADEM): Meet T-ADEM criteria without recurrence in years* III Definite ADEM (D-ADEM): Meet P-ADEM criteria, no recurrence for additional 10 years IV Tentative Recurrent ADEM (TR-ADEM): Initial bout + ≤ four total bouts* each meeting criteria for diagnosis T-ADEM V Probable recurrent ADEM (PR-ADEM): Meet TR-ADEM criteria followed by a hiatus of ≥ years without further recurrence* Not treated with immunomodulatory prophylaxis during those years without bouts VI Definite recurrent ADEM (DR-ADEM): Meet PR-ADEM criteria followed ≥ 10 additional years without recurrence Not treated with immunomodulatory prophylaxis during those 10 additional years (*Excepting taper-related recurrences) VII Type steroid-dependent idiopathic demyelinating illness (SDIPI) Recurrent cases not satisfying CD-MS or ADEM diagnostic categories Unavoidable recurrences provoked at same approximate threshold of steroid taper unless replaced with at least monthly high dose intravenous corticosteroids Excludes alternative diagnoses VIII Type steroid-dependent idiopathic demyelinating illness (SDIPI) Recurrent cases not satisfying CD-MS or ADEM diagnostic categories continued NICP_C05 04/05/2007 12:26PM Page 110 110 ROBERT S RUST Box 5.15 (Cont’d) Unavoidable recurrences provoked at same approximate threshold of steroid taper unless replaced with immunomodulatory interferon therapy Excludes alternative diagnoses IX Other idiopathic recurrent demyelinating illness (OIRDI) Recurrent cases not satisfying CD-MS, ADEM, R-ADEM, T-ADEM, or SDIDI criteria References Abramsky, O and Teitelbaum, D 1977 The autoimmune features of acute transverse myelopathy Ann Neurol, 2, 36– 40 Aicardi, J 1992 Diseases of the Nervous System in Childhood MacKeith Press, London Apak, R.A., Anlar, B and Saatci, I 1999 A case of relapsing acute disseminated encephalomyelitis with high dose corticosteroid treatment Brain Dev, 21(4), 279– 82 Arya, S.C 2001 Acute disseminated encephalomyelitis associated with poliomyelitis vaccine Pediatr Neurol, 24(4), 325 Atlas, S.W., Grossman, R.I., Goldberg, H.I et al 1986 MR diagnosis of acute disseminated encephalomyelitis J Comp Assist Tom, 10(5), 798– 801 Au, W.Y., Li, A.K., Cheung, R.T et al 2002 Acute disseminated encephalomyelitis after para-influenza infection post 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there is normal cerebrospinal fluid (CSF) cellularity with an increased CSF protein level Several variants have been reported Epidemiology Throughout the world, the annual incidence of GBS is 1.3 cases for 100,000, affecting children and adults GBS is the most common acute acquired neuropathy of childhood In adults the prevalence is higher in older patients (>75 years) as compared to younger patients (6 months CSF protein >45 g/dl, nerve biopsy (demyelination/ remyelination), NCS: motor conduction velocity may be normal but more commonly slowed Progression Diagnostic studies Diagnostic certainty Reflexes Tendency to symmetric, proximal, and distal weakness, though some have predominantly motor, sensory, or autonomic involvement Large-fiber sensory involvement Hyporeflexia or areflexia Dyck, 1975 Hyporeflexia or areflexia Minor criteria: only distal weakness or sensory loss Major criteria: symmetric, proximal, and distal weakness Saperstein, 2001 Definite: clinical phenotype, NCS, CSF, and biopsy Probable: clinical phenotype, NCS, and CSF Possible: clinical phenotype and NCS Definite: clinical major, NCS, and CSF Probable: clinical major, NCS or CSF, and biopsy Possible: (1) clinical major and one out of three diagnostic studies, or (2) clinical minor and two out of three diagnostic studies >2 months Mandatory: CSF (2 months Mandatory: CSF protein >45 g/dl, nerve biopsy (demyelination), NCS (Table 7.2) Supportive: CSF 2 months Inclusion criteria: CSF 2 months Elevated CSF protein is supportive, nerve biopsy (demyelination) may be supportive, NCS (Table 7.2) seen in most patients with weakness, though not in all patients Classic CIDP: symmetric, progressive, proximal, and distal weakness and predominantly large-fiber sensory impairment Variants: purely motor, predominantly sensory, asymmetric or multifocal weakness or sensory loss, cranial nerve involvement, only proximal or distal weakness Hyporeflexia or areflexia Neuropathy Association, 2003 Definite: clinical criteria (typical or atypical) and definite NCS (Table 7.2); or probable + at least one supportive criterion; or possible + at least two supportive criteria Probable: clinical criteria and probable NCS (Table 7.2); or possible CIDP + at least one supportive criterion Possible: clinical criteria and possible NCS (Table 7.2); or CIDP (definite, probable, possible) associated with concomitant diseases Typical: chronically progressive, stepwise, or recurrent symmetric proximal and distal weakness and sensory dysfunction of four extremities Cranial nerves may be affected Atypical: predominantly distal weakness; purely motor or purely sensory; asymmetric; focal; CNS involvement Typical: hyporeflexia or areflexia Atypical: normal in unaffected limbs >2 months Supportive criteria: elevated CSF protein with 80% LLN Same as AAN Same as AAN If CMAP amplitude ≥75% LLN Same as AAN If CMAP amplitude ≥20% LLN Same as AAN DML ≥150% @ULN DCMAP duration ≥9.0 ms DCMAP duration ≥9.0 ms Same as AAN >30% (median, ulnar, and peroneal nerves) Definite CB: ≥50% if CMAP amplitude ≥20% LLN¶ Probable CB: ≥30% if CMAP amplitude ≥20% LLN Definite: ≥1 of the following (a–g): (a) prolonged DML ≥2 nerves; (b) CVS ≥2 nerves; (c) prolonged F-min ≥2 nerves; (d) absent Fs ≥2 nerves plus §; (e) definite CB ≥2 nerves, or definite CB in nerve plus §; (f) TD ≥2 nerves; (g) prolonged DCMAP duration in one nerve plus § Probable: either probable CB ≥2 nerves, or probable CB in one nerve plus § Possible: As in definite, but in only one nerve CV ≤70% LLN¶ ENFS/PNS, 2005 >30% (median, ulnar, and peroneal nerves) ≥30% (forearm segment for median and ulnar, lower leg segment for peroneal nerves) Same as AAN Nerve conduction abnormalities ≥3 nerves with ≥1 nerve with demyelinating abnormalities (CVS, CB, TD, DCMAP duration, DML, or F-waves) Neuropathy Association, 2003 ¶: LLN: lower limit of normal; @ULN: upper limit of normal; §: plus another demyelinating parameter in one other nerve; ¥: CVS, prolonged DML, absent or prolonged F-min Distal CMAP (DCMAP) dispersion Severely prolonged distal motor latency (DML) Severely prolonged F-wave minimal latency (F-min) Absent F-waves Same as AAN >30% (median, ulnar, radial, tibial, and peroneal nerves) Temporal dispersion (TD) Same as AAN >15% (median, ulnar, and peroneal nerves) >40–60% amplitude drop, or >40 –50% area drop (1) DML >150% @ULN if CMAP amplitude 125% ULN if CMAP amplitude >80% LLN (1) F-min >150% @ULN if CMAP amplitude 120% ULN if CMAP amplitude >80% LLN ≥30% for the median, ulnar, and peroneal nerves, or ≥50% with Erb’s point stimulation Same as AAN (1) CV 65), CIDP typically has a slowly progressive distal pattern, unlike in younger patients, where proximal weakness is more common and a relapsing course is seen more frequently Predominantly sensory (31%) or equal sensory and motor involvement (51%) is more common in the elderly, and a pure motor syndrome is less common (17%) In contrast, adults (20–64) or juveniles (