immunotherapy- responsive dementias and … · cephalopathy, thyroid autoimmunity, and clinical...

IMMUNOTHERAPY-RESPONSIVEDEMENTIAS ANDENCEPHALOPATHIESAndrew McKeon, Vanda A. Lennon, Sean J. Pittock

ABSTRACT

The diagnosis of an autoimmune dementia requires the detection of objectiveimprovements in cognitive decline (usually subacute in onset with a fluctuatingcourse) after a course of immunotherapy. Serum and CSF antibody markers ofautoimmunity (particularly those with neural antigen specificity) as well as otherCSF markers of inflammation increase the suspicion for an autoimmune cause. Thedetection of neural autoantibodies should raise concern for a paraneoplastic eti-ology and may inform a targeted oncologic evaluation (eg, NMDA receptorantibodies are associated with teratoma). MRI, EEG, functional imaging, and neu-ropsychological evaluations provide objective evidence of neurologic dysfunction bywhich the success of immunotherapy may be measured. Most treatment in-formation emanates from retrospective case series and expert opinion. Nonethe-less, early intervention allows reversal of deficits in many patients. Chronictreatment is often required to maintain remission.

Continuum Lifelong Learning Neurol 2010;16(2):80–101.

INTRODUCTION

Little is more satisfying for a neurolo-gist than making a patient initially di-agnosed with a neurodegenerative de-mentia well again. When evaluating apatient with a primary concern of cog-nitive dysfunction, a central and oftenchallenging component of the diagno-sis is determining whether the patienthas a treatable (Table 4-1) or irrevers-ible (usually neurodegenerative) disor-der. Among rapidly progressive but po-tentially reversible disorders1 are theautoimmune encephalopathies (where

delirium is present) and autoimmunedementias (where there is no delirium,but other features considered atypicalfor a neurodegenerative disorder arepresent). Traditionally, neurologists havebeen reluctant to consider a diagnosisof an autoimmune cognitive disorderin the absence of delirium. However,some recent case series and clinico-serologic observations have suggesteda growing appreciation for autoimmuneneurologic disorders presenting withfeatures of dementia rather than de-lirium. Unfortunately, these potentially

Continuum Lifelong Learning Neurol 2010;16(2)

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Relationship Disclosure: Drs McKeon and Pittock have nothing to disclose. Dr Lennon has received license feepayments from RSR Limited/Kronus, Inc., for a patent to develop, market, and sell an autoantibody detectionkit. Dr Lennon’s compensation and/or research work has been funded in part by a grant to her institutionfrom a governmental organization and a nonprofit tax-exempt organization.Unlabeled Use of Products/Investigational Use Disclosure: Drs McKeon, Lennon, and Pittock discuss theunlabeled use of immunotherapies to treat autoimmune encephalopathies and dementias.

Copyright @ American Academy of Neurology. Unauthorized reproduction of this article is prohibited.

reversible conditions may be misdi-agnosed as being progressive neurode-generative (currently irreversible) dis-orders, with devastating consequencesfor the patient. Clinical clues that havehistorically helped clinicians identifypatients with autoimmune dementiasinclude a rapidly progressive or fluctu-ating course, the detection of inflam-

matory markers in the CSF, presence of aneural-specific autoantibody, and clinicalor serologic evidence of coexisting auto-immunity (in particular thyroid autoimmu-nity). For brevity’s sake, we will refer toautoimmune cognitive impairment with orwithout encephalopathy as autoimmunedementia throughout the text. The inci-dence and prevalence of autoimmune


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TABLE 4-1 Potentially Treatable Causes of Cognitive Impairment

Potentially Treatable Causesof Cognitive Impairment Examples

Autoimmune encephalopathiesand dementias

Immunotherapy-responsive disorders ofpresumed autoimmune etiology; somehave associated neural-specific antibodies(see Table 4-2)

Other inflammatoryCNS disorders

Multiple sclerosis, acute disseminatedencephalomyelitis, neurosarcoidosis

Vasculopathies CNS vasculitis, posterior reversibleleukoencephalopathy, subdural hematoma

Neoplastic Primary CNS lymphoma (includingintravascular and meningeal presentations)

Seizure disorders Nonconvulsive status epilepticus

Iatrogenic Benzodiazepines, antidepressants,antipsychotics, antiepileptics, analgesics

Toxic Alcohol, opiates, cocaine, amphetamines,organic solvents

Nutritional deficiency Vitamin B12, thiamine, folic acid

Psychiatric illness Anxiety, depression, psychosis

CNS infection Herpes simplex virus, human herpesvirus 6,HIV, fungal (eg, cryptococcus), mycobacterial,Whipple disease, neurosyphilis

Metabolic Respiratory, renal, or liver failure.Obstructive sleep apnea syndrome;mitochondrial disorders, eg, MELAS

Endocrine Disturbances in pituitary, thyroid, parathyroid,endocrine pancreatic, or adrenal function

CNS = central nervous system; HIV = human immunodeficiency virus; MELAS = (mitochondrial)myopathy, encephalopathy, lactic acidosis, and strokelike episodes syndrome.

KEY POINT

A Clinical clues

to identifying

patients with

autoimmune

dementias

include a

rapidly

progressive

course, the

detection of

inflammatory

markers in

the CSF,

presence of a

neural-specific

autoantibody,

and clinical or

serologic

evidence of

coexisting

autoimmunity.


dementias are unknown, but autoim-mune and inflammatory causes accountfor 20% of dementia in patients youngerthan 45 years of age.2 In recent years,neural-specific autoantibodies have beenidentified that have broadened the phe-notypic spectrum of autoimmune demen-tias. Voltage-gated potassium channel(VGKC) antibodies are an example.3,4

This field is very much in its infancy, anddata pertaining to the subject are limitedto mostly single cases or small case se-ries. Based on review of the literatureand our experience in a dedicated auto-immune neurology clinic, we will de-scribe in this chapter the clinical anddiagnostic features of autoimmune de-mentias and provide a practical guide forthe evaluation and treatment of patientswith these disorders.

DEFINITIONS

The confusing nomenclature pertain-ing to autoimmune dementias reflectsan evolving understanding of these dis-orders. Autoimmune dementias havebeen classified eponymously (eg, Morvansyndrome)5 syndromically (eg, progres-sive encephalomyelopathy with rigid-ity and myoclonus),6 serologically (eg,VGKC antibody–associated encephalop-athy)3 pathologically (eg, nonvasculitic au-toimmune meningoencephalitis),7or bya combination of these. Both Hashimotoencephalopathy8 and steroid-responsiveencephalopathy associated with autoim-mune thyroiditis9 refer to a triad of en-cephalopathy, thyroid autoimmunity, andclinical improvements with corticoste-roids. In some disorders, characteristicnoncognitive features are salient. Forexample, in a patient with a historyof branch retinal artery occlusions andhearing loss, as well as cognitive dif-ficulties, the steroid-responsive endo-theliopathy Susac syndrome should beconsidered.10 Multifocal symptoms andsigns that are common in Susac syn-drome include headache, psychiatric dis-

turbances, memory loss, and rapidly pro-gressive dementia.

Other CNS disorders that are ofunknown cause but usually classifiedas inflammatory may present as rapidlyprogressive dementia (Table 4-1). Eachhas well-characterized clinical, radio-logic, and pathologic diagnostic crite-ria and recommended treatments, andthus needs to be excluded when con-sidering a diagnosis of autoimmune de-mentia. More commonly encounteredexamples include CNS vasculitis, mul-tiple sclerosis (MS) and sarcoidosis. CNSvasculitis (also known as primary angiitisof the CNS) is characterized pathologi-cally by multifocal vascular inflamma-tion with predilection for small arteriesin leptomeninges. Some patients havea coexisting amyloid angiopathy.11 Itsvariable clinical features include head-ache, delirium, and rapidly progres-sive dementia. An MS relapse may becharacterized by subacute cognitive de-cline with delirium and impaired at-tention, and subsequent improve-ments may occur during remission.12

CNS disease is a serious and poten-tially devastating complication of sar-coidosis, which is an inflammatorymultisystem disorder that affects thenervous system in 5% to 15% of patients.Although noncognitive syndromes (in-cluding cranial neuropathies and asep-tic meningitis) are its most commonCNS presentations, a subset of patientshas amnesia and other cognitive defi-cits.13 As the disease presentations areprotean, solitary CNS sarcoidosis isoften difficult to diagnose without abrain biopsy.

In the interest of simplicity we pro-pose the following as the essence ofautoimmune dementia: (1) clinical, ra-diologic, or serologic evidence support-ing an autoimmune etiology; (2) othercauses of dementia, particularly revers-ible causes excluded (Table 4-1); and(3) an objectively documented favorableresponse to immunotherapy.


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KEY POINTS

A Autoimmune

and

inflammatory

causes account

for 20% of

dementia in

patients

younger than

45 years of age.

A Other CNS

disorders that

are of unknown

cause but

usually

classified as

inflammatory

may present

as rapidly

progressive

dementia.

More commonly

encountered

examples include

CNS vasculitis,

multiple sclerosis,

and sarcoidosis.

"AUTOIMMUNE DEMENTIAS


COGNITIVE DECLINE ANDAUTOIMMUNITY: KEY POINTS

Diagnostic Clues

The following are worth consideringwhen an autoimmune etiology is sus-pected for a patient presenting with anew-onset neurologic disorder.

o The clinical manifestations ofneurologic autoimmunity arediverse and often multifocal.

o A personal or family historyof autoimmunity orseropositivity for organ-specific(or non–organ-specific)autoantibodies is a risk factor foran autoimmune dementia.

o Detection of a neural-specificautoantibody serves as a markerof neurologic autoimmunity.

o An informative profile ofneural-specific autoantibodiesaids the identification of aparaneoplastic etiology for anautoimmune dementia.

o A trial of immunotherapy mayserve as a valuable ‘‘diagnostic test.’’

The clinical manifestations ofneurologic autoimmunity are di-verse and often multifocal. Whilecertain disorders have been syndromi-cally associated with certain autoanti-body markers (eg, limbic encephalitisand VGKC autoantibodies),4 a broaderneurologic spectrum inevitably emergesover time through individual case re-ports14 or by systematic serologic eval-uation of large numbers of patientsnot selected by neurologic syndrome(Case 4-1).3 For example, VGKC an-tibodies were initially considered tobe specific for autoimmune limbic en-cephalitis or disorders of peripheralnervous hyperexcitability, but over timeother presentations have been reported,including a rapidly progressive coursemimicking Creutzfeldt-Jakob disease.15

A personal or family history ofautoimmunity or seropositivity fororgan-specific (or non–organ-specific)autoantibodies is a risk factor foran autoimmune dementia. Multipleautoimmune disorders may occur inthe same patient, and individuals with


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Case 4-1An 82-year-old man presented to the emergency department with a6-month history of progressive deterioration in behavior. He had becomemore irritable, had poor self-care, lacked insight, and was prone toaggressive outbursts. His examination was remarkable for repetitivestereotyped facial grimacing and intermittent aphasia. Although hisMini-Mental State Examination (MMSE) score was 27/30 and demonstratednormal recall, the Frontal Assessment Battery demonstrated deficits inmental flexibility, motor programming, and inhibitory control (11/18).MRI showed mild generalized atrophy, but fluorodeoxyglucose PETdemonstrated bifrontal hypometabolism. Serum VGKC autoantibodywas detected. The diagnosis made was VGKC-antibody-associatedencephalopathy with frontotemporal phenotype. Within 3 weeks ofstarting prednisolone (70 mg/d), the syndrome improved considerablyand the Frontal Assessment Battery score was 17/18. After 6 months oftapering prednisolone dose, the patient was still mildly disinhibited buthad resumed living independently.

Comment. This case illustrates (1) that the spectrum of cognitivedisorders associated with VGKC autoimmunity extends beyond limbicencephalitis and (2) that screening with the MMSE alone may not detectcognitive deficits referable to the frontal lobes.

KEY POINT

A A personal or

family history of

autoimmunity

or seropositivity

for organ-specific

(or non–organ-

specific)

autoantibodies is

a risk factor for

an autoimmune

dementia.


an autoimmune disease are at higherrisk of developing a second autoim-mune disorder.16 For example, just asrheumatoid arthritis may occur in apatient with type 1 diabetes mellitus,so may autoimmune thyroiditis (a verycommon form of autoimmunity) andan autoimmune dementia (a relativelyuncommon form of autoimmunity) oc-cur in the same patient. Thus, the pres-ence of autoimmune thyroiditis reflectsa risk for developing other autoimmunediseases, including an autoimmune de-mentia. The detection of an organ-specific (eg, thyroid) or non–organ-specific antibody (eg, nuclear or ex-tractable nuclear antigen) in a patientwith an autoimmune dementia doesnot imply pathogenicity of the anti-body detected.

Detection of a neural-specific au-toantibody serves as a marker ofneurologic autoimmunity. Antibod-ies directed at cell-surface antigens(eg, VGKC antibodies) may be patho-genic, while antibodies directed at anintracellular antigen (eg, antineuronalnuclear antibody type 1 [ANNA-1, oranti-Hu]) are more likely markers of aT-cell mediated disease.17

An informative profile of neural-specific autoantibodies aids the iden-tification of a paraneoplastic etiol-ogy for an autoimmune dementia.Antibodies with neural specificity havevarying degrees of paraneoplastic sig-nificance. For examples, see the latersection ‘‘Testing.’’

A trial of immunotherapy mayserve as a valuable ‘‘diagnostic test.’’The diagnosis of autoimmune demen-tia is somewhat dependent on clinicalimprovements obtained with immuno-therapy. Therefore, in the evaluationof a patient with suspected autoim-mune dementia, baseline objective clini-cal, electrophysiologic, radiologic, andneuropsychological testing providesreference points for evaluating clinicalimprovement with immunotherapies.

SYMPTOMS OF AUTOIMMUNEDEMENTIA

Patients with autoimmune dementiasusually present with an acute or sub-acute disorder of memory, thinking, orbehavior. A common cognitive disor-der seen in an autoimmune context islimbic encephalitis. This is generallya fluctuating confusional state accom-panied by one or more symptomsof memory loss, agitation, halluci-nations, and focal seizures.18 A vari-ety of autoantibody accompaniments(Table 4-23,4,14,15,19–34) have been de-scribed. However, one or more ofthe full range of dementia symptomsmay be encountered, including impair-ments in learning and retaining newinformation; disturbances in language,behavior, orientation, reasoning andpraxis (Case 4-2); and difficulty han-dling complex tasks. Impairments inattention and consciousness (delirium)are common in autoimmune dementiasbut are not always present. Fluctuationsin cognitive abilities from day to day arecommon in autoimmune dementias butmay also be observed in patients withneurodegenerative disorders, particular-ly diffuse Lewy body disease.35 Althoughuncommon, a history of spontaneousremission suggests an autoimmune eti-ology, but remission also may occur intoxic, metabolic, and psychogenic dis-orders, and depression.

PERSONAL OR FAMILY HISTORYOF AUTOIMMUNITY OR CANCERAND CANCER RISK FACTORS

This information is a valuable clue toan autoimmune basis for dementia. Anunsuspected cancer, new or recurrent,may manifest neurologically as anautoimmune dementia (eg, in patientswho are seropositive for VGKC anti-body or NMDA receptor [NMDAR] anti-body [Case 4-3]). Smoking history anda review of systemic symptoms (eg,weight loss, altered bowel habit) areall potentially informative.


84

KEY POINTS

A Detection of a

neural-specific

autoantibody

serves as a

marker of

neurologic

autoimmunity.

A When an

autoimmune

etiology is

suspected for a

patient presenting

with a new-onset

neurologic

disorder, a trial of

immunotherapy

may serve as

a valuable

diagnostic test.

A Patients with

autoimmune

dementias

usually present

with an acute

or subacute

disorder of

memory,

thinking, or

behavior.

A Personal or

family history of

autoimmunity

or cancer and

cancer risk

factors are

valuable clues to

an autoimmune

basis for

dementia.




85

TABLE 4-2 Antibodies With Specificity for Neural Antigens, AccompanyingCognitive Disorders, and Other Reported Neurologic Findings andOncologic Associations

AntibodyReported CognitiveDisorders

Other NeurologicFindings Cancer Association References

VGKC Limbic encephalitis,amnestic syndrome,executive dysfunction,personality change,disinhibition

Hypothalamic disorder,brainstem encephalitis,ataxia, extrapyramidaldisorders, myoclonus,peripheral andautonomic neuropathy/hyperexcitability

Small cell lungcarcinoma; thymoma;adenocarcinoma ofbreast, prostate

3,4,14,15

NMDAreceptor

Amnestic syndrome Anxiety, psychosis,seizures, extrapyramidaldisorders, opsoclonus,myoclonus

Teratoma, usuallyovarian

19

GAD65 Limbic encephalitis,other encephalitides

Stiff person syndrome,stiff person phenomena,ataxia, seizures,brainstem encephalitis,ophthalmoplegia,parkinsonism,myelopathy

Thymoma, lungcarcinoma

20,21

AMPAreceptor

Limbic encephalitis Nystagmus, seizures Thymic tumors, lungcarcinoma, breastcarcinoma

22

GABAB

receptorLimbic encephalitis Orolingual dyskinesias Small cell lungcarcinoma,

other neuroendocrineneoplasia

23

ANNA-1(anti-Hu)

Limbic encephalitis Brainstem encephalitis,autonomic neuropathies,sensory neuronopathy,sensorimotor neuropathy

Small cell carcinoma,neuroblastoma,thymoma

24,25

ANNA-2(anti-Ri)

Dementia, limbicencephalitis

Brainstem encephalitis,myelopathy, peripheralneuropathy

Small cell carcinoma orbreast adenocarcinoma

26

ANNA-3 Limbic encephalitis Brainstem encephalitis,myelopathy, peripheralneuropathy

Small cell carcinoma 27

AGNA(SOX-1)

Limbic encephalitis Neuropathy,Lambert-Eaton syndrome


PCA-2 Limbic encephalitis Ataxia, brainstemencephalitis,Lambert-Eaton syndrome,peripheral andautonomic neuropathies


continued on next page


CLINICAL EXAMINATION

A bedside evaluation of cognitive func-tion, such as the MMSE36 or KokmenShort Test of Mental Status,37 shouldreveal impairments in one or morecategories of attention, memory, rea-soning, calculation, and praxis. The pres-ence of multifocal neurologic symptomsand signs is a valuable clue to thepossibility of an autoimmune etiology.Rapid evolution of a cognitive disorder,with accompanying epilepsy, ataxia, par-kinsonism, brainstem signs, myelop-athy, or a peripheral nervous system dis-order, should trigger consideration of anautoimmune dementia as well as toxic,nutritional, metabolic causes, or otherinflammatory disorders (Table 4-1).Careful documentation of objective ab-normalities provides a baseline for com-parison when reevaluating the patientafter a trial of immunotherapy.

TESTING

The four components of testing in apatient with a suspected autoimmunedementia are:

(1) Exclusion of other causes ofcognitive decline, particularly othertreatable disorders

(2) Objective documentation ofcognitive and other neurologicabnormalities

(3) Testing for further clues toan autoimmune (idiopathic orparaneoplastic) diagnosis

(4) Evaluation for cancer

Exclusion of Other Causes ofCognitive Decline, ParticularlyOther Treatable Disorders

Other causes of cognitive decline needto be considered, including degenera-tive disorders, inflammatory disorders,


86

TABLE 4-2 Continued

AntibodyReported CognitiveDisorders

Other NeurologicFindings Cancer Association References

CRMP-5(anti-CV2)

Subacute-onsetdementia, personalitychange, aphasia

Depression, chorea, ataxia,myelopathy, radiculopathy,neuropathy, cranialneuropathy, Lambert-Eaton syndrome

Small cell carcinoma,thymoma

30

Amphiphysin Limbic encephalitis,aphasia, other subacute-onset dementias

Stiff person phenomena,myelopathy, neuropathy

Breast adenocarcinoma,small cell carcinoma

31

Ma/Taproteins(usually Ma2,sometimesMa1)

Limbic encephalitis Hypothalamic disorder,brainstem encephalitis

Testis, small cellcarcinoma, other solidorgan cancers

32

NMO-IgG Reports ofencephalopathiesin children

Optic neuritis, transversemyelitis

Some reports ofthymoma and othersolid tumors

33,34

VGKC = voltage-gated potassium channel; NMDA = N-methyl-D-aspartate; GAD65 = glutamic acid decarboxylase; AMPA =�-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid; GABA = �-aminobutyric acid; ANNA = antineuronal nuclearantibody; AGNA = antiglial nuclear antibody; PCA = Purkinje cell cytoplasmic antibody; CRMP-5 = collapsin-responsemediator-protein 5; NMO = neuromyelitis optica.




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Case 4-2A 79-year-old woman presented with rapid loss of function and twitching of the rightupper extremity. The previous year she had been treated for locally invasive breastadenocarcinoma. Examination showed prominent myoclonus and ideomotor apraxia ofthe right upper extremity. Corticobasal degeneration (CBD) was initially considered,but the rapidity of symptom onset and decline in neurologic function was atypical. A cranialMRI revealed T2 signal abnormality in the left superior-posterior frontal lobe (Figure 4-1),with mild gyral swelling and subtle gyral enhancement. EEG demonstrated epilepsiapartialis continuaemanating from theleft perirolandicarea. CSF had fiveoligoclonal bandsbut normal whitecell count. Adiagnosis of focalparaneoplasticencephalopathymimicking CBDwas made.Clinical stabilizationfollowed a 5-daycourse of IVmethylprednisolone.Next she received6 monthlypulsed IV doses ofcyclophosphamide.The MRI abnormalitylargely resolved,but the patientcontinued to havefrequent focal motorseizures of the rightupper extremity.

Comment. This caseillustrates (1) thatthe presentation ofan autoimmunedisorder of praxismay mimic aneurodegenerativedisease, in thiscase CBD, and(2) that featuresatypical for CBDraise suspicion foran autoimmunecause.

FIGURE 4-1 Radiologic improvements in two patients with autoimmune dementias.A patient with radiologic evidence of voltage-gated potassium channelantibody–associated limbic encephalitis (A, arrow) had radiologic

(as well as clinical) improvement in T2-fluid-attenuated inversion recovery signalabnormalities after corticosteroid therapy (B). The patient in Case 4-2 with a corticobasaldegeneration-like presentation (C ) had an axial T2-weighted superior-posterior left-sidedfrontal abnormality (arrow), which improved considerably after treatment withcorticosteroids (D).

Panels C and D reprinted with permission from McKeon A, Ahlskog JE, Britton JA, et al. Reversibleextralimbic paraneoplastic encephalopathies with large abnormalities on magnetic resonance images. ArchNeurol 2009;66(2):268–271. Copyright # 2009, American Medical Association. All rights reserved.


vasculopathies, neoplasia, seizure dis-orders, drug effects, nutritional deficien-cies, infections, metabolic disorders, andendocrine disturbances (Table 4-1).

Objective Documentationof Cognitive and OtherNeurologic Abnormalities

These evaluations enable characteriza-tion of multifocal accompaniments ofautoimmune dementia in an individualpatient, and provide a pretreatmentclinical baseline.

Neuropsychological Testing

Although not required for a diagnosisof autoimmune dementia, detailed as-sessment of cognitive deficits by neuro-psychological testing provides objectiveevidence where impairments are mild

(Case 4-4) and not detectable by bed-side testing. It also may reveal potentialmitigating factors, such as depression.

Neuroimaging

Magnetic resonance imaging. MRImay reveal abnormalities in T2-signalcharacteristics atypical for neurode-generative disorders. Mesial temporallobes are a common location for T2-signal abnormalities in autoimmunedementias, particularly in patients withVGKC autoantibodies. However, largeextratemporal abnormalities are some-times observed.38 Subtle white matteror gyriform enhancement may be seen,but avid enhancement should raisesuspicion for a primary tumor (includ-ing CNS lymphoma), sarcoidosis, or CNSvasculitis. The MRI abnormality typical of


88

Case 4-3A 55-year-old man with no significant previous medical history presentedwith abrupt onset of memory difficulty 2 years previously. The firstepisode was characterized by sudden inability to remember spokendirections and difficulty remembering events 6 weeks later. The patienthad slow improvements after each event but never returned to normal.Personal history was remarkable for graying of hair in late teen years(poliosis). He had a sister with systemic lupus erythematous (SLE) anda strong family history of thyroid autoimmunity. The Kokmen Short Test ofMental Status revealed a score of 36/38 (2/4 for recall). MRI brain scanshowed mild generalized cerebral atrophy, and EEG showed generalizedmild slowing. Neuropsychological evaluation revealed moderateimpairments in learning and memory; the profile was most consistent withamnestic mild cognitive impairment. Evaluation for serologic and CSFmarkers of autoimmunity was negative. Atypical amnestic mild cognitiveimpairment was diagnosed, but, because of the family history ofautoimmunity, a course of IV methylprednisolone was initiated (1000 mgfor 3 consecutive days, followed by 1000 mg weekly for 10 weeks).At follow-up (2 weeks after completing methylprednisolone treatment,and 4 months after initial neuropsychological evaluation) the patientreported dramatic improvement of cognition, recall was 4/4 per theKokmen test, and learning and memory were improved significantlyon neuropsychological reevaluation. There had been no recurrence ofthese cognitive problems 14 months after completing immunotherapy.

Comment. This case demonstrates that the spectrum of autoimmunedementias may include mild cognitive impairment, as well as floridencephalopathy. Neuropsychological evaluations performed beforeand after immunotherapy allowed objective assessment of the responseto treatment.




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Case 4-4An adolescent girl presented with a few days of right hand numbness, arm pain, andschool-related paranoia, beginning 3 days after mild upper respiratory symptoms. She was notfebrile but appeared ill, had difficulty finding words, and speech was mildly slurred. Onadmission to intensive care, she developed involuntary repetitive hand movements predominatelyon the right, and periods of agitation with unresponsiveness, mutism, flailing of the rightarm, drooling, and enuresis. Between episodes she appeared lucid. The CSF contained 63white blood cells per �L, with normal protein and glucose concentrations. EEG demonstratedleft-sided background slowing. Brain MRI after contrast administration showed minimal sulcalenhancement. Haloperidol therapy was started to treat agitation. Hyperthermia developed4 days later. On hospital admission she had neck dystonia, body rigidity, and opisthotonicposturing. Serum creatinine kinase level was normal. In periods of agitation the systolic bloodpressure increased to 150 mm Hg. She was mute, appeared frightened, and was intermittentlyable to follow simple commands. Reflexes were brisk with unsustained bilateral clonus;she exhibited intermittent waxy catatonia. Lorazepam and a loading dose of levetiracetamwere administered for suspected status epilepticus. Video EEG showed left-sided slowingwithout epileptic activity; episodes of masticatory movements and right eye deviation werecaptured without electrographic correlate. Infrequent episodes of oxygen desaturationwere recorded, but she did not require intubation. On day 15 of the illness, NMDA receptorantibodies were detected in CSF (Figure 4-2). A 5-day course of simultaneous IV immunoglobulin

(IVIG) and methylprednisolone wasstarted. Screening for ovarian teratomaand other systemic neoplasia wasnegative. The dystonia improved within1 week, and she could stand and walkwith shuffling gait, but remaineddisinhibited, impulsive, hyperoral,and hypersexual. Initial speech wascharacterized by echolalia and incoherentbabbling but progressed to appropriatefull sentences. Emotional labilitycontinued, with frequent tearfulness; sleepbecame more erratic with nighttimeawakenings but improved with clonidine.After transfer to a rehabilitation facilityon day 20, episodic agitation, crying, andscreaming continued. Six weeks aftersymptom onset, speech, behavior, andmobility were substantially improved.Eight weeks after symptom onset,neuropsychological testing revealedmild deficits in processing speed, butadvanced intellectual ability waspreserved. Periodic follow-up and MRIscreening for ovarian teratoma continued.

Comment. This case illustrates the classic neuropsychiatric presentation and appropriateoncologic screening (59% have cancer, usually teratoma19) in an adolescent girl with NMDAreceptor antibodies and the potential in some cases for good neurologic recovery with a shortcourse of immunotherapy.

Case 4-4 contributed by Josep Dalmau, MD, PhD, Department of Neurology, University of Pennsylvania.

FIGURE 4-2 Cultures of nonpermeabilized live rathippocampal neurons incubated with theCSF of the patient in Case 4-3 (diluted at

1:10) shows extensive cell-surface immunolabeling withN-methyl-D-aspartate receptor antibodies. The figure is based onindirect immunofluorescence (picture takenwithoil lens,�800).

Figure courtesy of Josep Dalmau, MD, PhD, University of Pennsylvania.


Susac syndrome preferentially involvesthe central corpus callosum.10 Rapidlyresolving large hemispheric T2 abnor-malities should raise concern for a mito-chondrial disorder, including mitochon-drial myopathy, encephalopathy, lacticacidosis, and strokelike episodes (MELAS).Nonenhancing large T2-signal abnor-malities should raise consideration ofprogressive multifocal leukoencephal-opathy. Rarer, but striking, T2-signalabnormalities usually associated with

Creutzfeldt-Jakob disease, including gyri-form T2-signal changes, have been ob-served in patients with VGKC antibodies(Figure 4-3).

Functional imaging. PET or SPECTmay reveal areas of abnormal brainmetabolism corresponding to clinicalsymptoms. In patients with a coexistingseizure disorder of new onset, theseimages may give the false impression ofa malignant CNS neoplasm, particularlyin patients with VGKC autoimmunity.


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FIGURE 4-3 Brain magnetic resonance images of a patient with immunotherapy-responsivevoltage-gated potassium channel (VGKC) autoimmunity and renal oncocytomaillustrate increased signal in the left anterior cingulate gyrus and insular cortex

on diffusion-weighted imaging (A, arrows) and fluid-attenuated inversion recovery sequences(B and C, arrows). Indirect immunofluorescence testing of the patient’s serum revealed IgGbinding to VGKC-rich synapses in mouse cerebellar cortex (D).

ML = molecular layer; GL = granular layer; PC = Purkinje cells (unstained).

Reprinted with permission from Geschwind MD, Tan KM, Lennon VA, et al. Voltage-gated potassium channelautoimmunity mimicking Creutzfeldt-Jakob disease. Arch Neurol 2008;65(10):1341–1346. Copyright # 2008,American Medical Association. All rights reserved.

KEY POINT

A PET or SPECT

may reveal

areas of

abnormal brain

metabolism

corresponding

to clinical

symptoms.



Electrophysiological testing. Al-though abnormalities detected are notspecific for an autoimmune etiology,EEG, like functional imaging, may aidcharacterization of the disorder in anindividual patient and provide a pre-treatment baseline. Common abnor-malities detected on EEG include focalor generalized slowing or spike- andslow-wave epileptiform discharges. Me-sial temporal abnormalities are oftenobserved in autoimmune dementias,but extratemporal abnormalities alsohave been reported.38

Resolution of an EEG, MRI, or func-tional imaging abnormality after immuno-therapy serves as an objective markersupporting subjective improvements(Figures 4-1 and 4-4, Case 4-3).

Testing for Further Clues to anAutoimmune (Idiopathic orParaneoplastic) Diagnosis

Autoantibody testing. Detection ofautoantibodies in serum or CSF aug-ments the information obtained in the

clinical history. An informative auto-antibody profile may include neural andnon-neural IgG markers. Seropositivityfor non-neural autoantibodies does notconfirm a diagnosis of an autoimmunedementia, but does support con-sideration of an autoimmune patho-genesis and may trigger additionalserologic evaluation and a trial of im-munotherapy. For example, detectionof thyroperoxidase or thyroglobulinautoantibodies in a patient with cogni-tive symptoms does not confirm adiagnosis of an autoimmune cognitivedisorder (so-called Hashimoto enceph-alopathy) but is a supportive finding.

In a patient presenting with cognitivedysfunction, seropositivity for antinu-clear antibodies and double-strandedDNA antibodies will raise suspicion forlupus cerebritis (or CNS lupus), a poorlyunderstood disorder classified underthe umbrella of neuropsychiatric lupus(which includes diverse diagnoses, fromstroke to peripheral neuropathy in thesetting of SLE).39 Primary neurologicpresentations account for 25% of lupus


91

FIGURE 4-4 Axial PET-CT images of brain of a 60-year-old woman who presentedwith rapid-onset generalized cognitive dysfunction and psychosis aftermastectomy for breast adenocarcinoma. PET-CT demonstrated global

hypometabolism before treatment (A, yellow and green colors). After 9 months’ treatmentwith IV immunoglobulin, improvements in clinical and radiologic parameters were noted(B, red color predominates in the frontal lobes, but some hypometabolism persisted posteriorly).

Figure courtesy of Eoin Flanagan, MBBch, Mayo Clinic.

KEY POINTS

A EEG, like

functional

imaging,

may aid

characterization

of the disorder

in an individual

patient and

provide a

pretreatment

baseline.

A Detection of

autoantibodies

in serum or CSF

augments the

information

obtained in the

clinical history.

An informative

autoantibody

profile may

include neural

and non-neural

IgG markers.


cerebritis cases.40 Headache, seizures,and memory impairment are common,but movement disorders (including par-kinsonism and myoclonus) have alsobeen reported.40 Despite sporadic litera-ture reports,41 no autoantibody markerhas been confirmed to reliably informwhich patients with SLE will developcerebritis. Autoimmune dementia canarise in the setting of other non–organ-specific autoimmune diseases, includingSjogren syndrome.42 Similarly, no spe-cific biomarker has been identified forCNS disease in that context.

The detection of a neural-specificantibody in serum or CSF (Table 4-2)aids the diagnostic process by: (1) raisingsuspicion for an autoimmune neurologicdisorder, and (2) raising the possibility ofa paraneoplastic cause for that autoim-mune disorder. Clinical syndromes thatare recognized with certain antibodymarkers include limbic encephalitis withVGKC antibodies (Figure 4-1), ANNA-1(anti-Hu)25 (Figure 4-5), and �-amino-3-hydroxy-5-methyl-4-isoxazolepropionicacid (AMPA) receptor antibodies22; fluc-

tuating dense hemiplegia with com-plete recovery and thyroid autoanti-bodies8; and early psychiatric features(anxiety, agitation, delusions, visual andauditory hallucinations) with NMDA re-ceptor antibody (Case 4-4,Figure 4-2).19

However, the clinical phenotype asso-ciated with any given neural auto-antibody is usually broader than theinitially described ‘‘classic’’ neurologicassociations.17

The positive predictive values forrates of cancer detection (and cancertype) vary from 33% for VGKC anti-bodies (diverse cancer types)3 to over80% for ANNA-1 (almost always small-cell lung carcinoma).25 Comprehen-sive testing for neural-specific autoan-tibodies is more informative thantesting for individual antibodies, be-cause the neurologic manifestations ofparaneoplastic autoimmunity are pro-tean and not limited to presentationscited in case reports. An individualpatient’s profile of coexisting autoanti-bodies may have high predictive valuefor a specific cancer. For example,


92

FIGURE 4-5 Antineuronal nuclear autoantibody type 1 (ANNA-1, anti-Hu). Indirectimmunofluorescence of mouse cerebellum and gut (�400): immunoreactivityin neuronal nuclei and perikarya in the granular layer (GL, A), molecular layer(ML, A), and Purkinje cells (PC, arrow, A) of cerebellum, and ganglionic neuronsof myenteric plexus (MP, arrow, B).

KEY POINT

A The positive

predictive

values for rates

of cancer

detection (and

cancer type)

vary from

33% for

voltage-gated

potassium

channel

antibodies

(diverse cancer

types) to over

80% for

ANNA-1.



amphiphysin antibody in a womanmay be associated with breast carcino-ma or small-cell lung carcinoma, eitherpulmonary or extrapulmonary in ori-gin.43 Antibody tests performed onserum alone are often sufficiently in-formative, but CSF testing sometimesincreases the diagnostic yield (eg,collapsin-response mediator-protein 5[CRMP-5]-IgG). However, in the caseof NMDAR antibodies CSF is some-times more informative than serum.Simultaneous testing of serum andCSF is therefore recommended.

Other CSF parameters. Furtherclues to an autoimmune etiology for acognitive disorder may be found onCSF evaluation. Elevated protein con-centration (greater than 100 mg/dL),mild CSF pleocytosis, abnormal numb-ers of CSF-exclusive oligoclonal bands,and elevated IgG index and synthesisrate all support an autoimmune etiol-ogy. These CSF findings are encoun-tered in many inflammatory CNS dis-orders, including MS. Oligoclonal bandsare detected in 7% of patients with path-ologically proven primary neurodegen-erative disorders44 and in 4% of patientswith Creutzfeldt-Jakob disease.45

Testing for Cancer

Suspicion for a paraneoplastic cause ofan autoimmune cognitive disorder mayarise because of a risk factor identifiedin the history (eg, smoking or a familyhistory of cancer) or because one ormore antibodies detected have a knowncancer association. In this setting, screen-ing for cancer is warranted. In additionto a general clinical examination, CT ofchest, abdomen, and pelvis in all patients,mammography in women, and testicularultrasound and prostate-specific antigen(PSA) in men should be performedwhere appropriate. Certain antibodieswith a particular specificity for cancer(eg, NMDAR antibody and teratoma)may further refine the diagnostic eval-

uation. For paraneoplastic neurologicdisorders, PET imaging alone, or incombination with anatomic data (PET-CT), increases the cancer diagnosticyield by 20% when all standard evalua-tions (eg, whole-body CT scan) havebeen uninformative.46

TREATMENT

No definitive evidence-based medicinesupports the use of immunotherapyfor the treatment of autoimmune de-mentias. Available data emanates fromexpert opinion,47 retrospective caseseries,4,20 and individual case reports.One prospective open-label study eval-uated the efficacy of immunotherapyin 20 patients with paraneoplastic neu-rologic disorders, of whom only fivehad cognitive impairment48; improve-ments were observed in two of threepatients who received oral cyclophos-phamide and plasma exchange, andin none of two patients who receivedplasma exchange and conventional can-cer chemotherapy. Despite paucity offormal evidence, a rational therapeuticapproach can be applied using treat-ments that have been successfully ap-plied in a variety of autoimmune dis-orders. The authors typically use aprotocol divided into acute (‘‘diagnos-tic’’) and chronic therapeutic phases.This approach is extrapolated from acombination of clinical experience andfrom knowledge of the therapeutic ap-proach to other autoimmune disorders,but is not evidence based (Table 4-3,Figure 4-6).

Acute Therapy—TheDiagnostic Test

A response to immunotherapy in theacute treatment phase has diagnosticas well as therapeutic importance. Theauthors generally initiate a trial of high-dose pulse IV corticosteroids therapy(Table 4-3). IVIG is a useful alternative


93

KEY POINTS

A Further clues to

an autoimmune

etiology for a

cognitive

disorder may be

found on CSF

evaluation.

A Suspicion for a

paraneoplastic

cause of an

autoimmune

cognitive

disorder may

arise because of

a risk factor

identified in

the history or

because one

or more

autoantibodies

detected have

a known cancer

association.

Certain

autoantibodies

with a particular

specificity for

cancer may

further refine

the diagnostic

evaluation.

A PET imaging

alone, or in

combination

with anatomic

data (PET-CT),

increases the

cancer

diagnostic yield

by 20% when

all standard

evaluations

have been

uninformative.


to corticosteroid infusions for patientswho cannot tolerate corticosteroids,have diabetes mellitus, or are at riskfor diabetes (eg, patients seropositivefor GAD65 or IA-2 autoantibodies,which are markers of susceptibility to

autoimmune type 1 diabetes). Alternate-week dosing with IVIG is reasonablesince the elimination half-life of humanIgG is approximately 2 to 3 weeks.Plasma exchange is also a useful treat-ment for rapid reversal of cognitive


94

TABLE 4-3 Some Therapeutic Options for Autoimmune Dementias

Drug Dose Route Frequency

Some Commonand SevereSide EffectsEncountered

TherapeuticPhase

Methylprednisolone 500 mg to1000 mg or15 mg/kg to30 mg/kg

IV Daily for 3 to5 days, followedby weekly for4 to 8 weeks

Insomnia, increasedappetite, psychiatricdisturbance,Cushing syndrome,skin thinning,diabetes,hypertension,cataracts, recurrentinfections,osteoporosis, hipavascular necrosis.

Acute andchronic, thentaper

Addisonian crisison rapid withdrawalof physiologic dosesof corticosteroid.

Immunoglobulin 0.4 g/kg IV Daily for 3 days,then alternateweeks for 6 to8 weeks

Headache, asepticmeningitis, deepvenous thrombosis,anaphylaxis, renalfailure.

Acute andchronic

Azathioprine 1 mg/kg/d to2 mg/kg/d

PO Two dailydivided doses

Hypersensitivityreaction, rash,myelotoxicity.

Chronic

Mycophenolatemofetil

500 mg/d to2000 mg/d

PO Two dailydivided doses

Diarrhea,hypertension,myelotoxicity, CNSlymphoma, renalfailure.

Chronic

Cyclophosphamide 500 mg/m2/mo(IV) to1000mg/m2/mo(IV)1 mg/kg/dto2mg/kg/d (PO)

IV orPO

Monthly (IV)Daily (PO)

Alopecia, mucositis,infertility,myelotoxicity,hemorrhagic cystitis.

Chronic

IV = intravenous; PO = by mouth; CNS = central nervous system.



symptoms in patients with autoimmunedementias49 but is generally reservedfor critically ill patients or when cortico-steroids or IVIG is poorly tolerated.

After an initial 4- to 8-weeks trial oftherapy, the patient should be reeval-uated for subjective and objective evi-dence of clinical improvement, pref-erably by the same physician and inthe same institution or clinic to assuretest-retest consistency. This is particu-larly important for mental status andneuropsychological testing, in whichthe instruments of measure may differfrom institution to institution. Patientswho report feeling better followingcorticosteroid therapy may lack objec-tive evidence of improvement. In

patients who lack objective evidenceof improvement, a trial of IVIG couldbe considered, again with subsequentevaluations.

In a recent study, the authors ex-amined the clinical course and pre-dictors of improvement in 75 patientswith a predominant cognitive disorderwho received immunotherapy becausethe treating clinician considered thepossibility of an autoimmune etiology.50

Improvements were documented in 65%of cases. Statistically significant predic-tors of immunotherapy-associated im-provement included a subacute onset,fluctuating course, shorter delay totreatment, detection of a cation channel-specific autoantibody (VGKC, calcium

95

FIGURE 4-6 A non–evidence-based algorithm for the therapeutic management of a patient with a suspectedautoimmune dementia or encephalopathy.

MRI = magnetic resonance imaging; PET = positron emission tomography; EEG = electroencephalogram;CSF = cerebrospinal fluid; IV = intravenous; IVIG = intravenous immunoglobulin.

KEY POINT

A After an initial

trial of therapy,

patients with

autoimmune

dementias

should be

reevaluated for

subjective and

objective

evidence of

clinical

improvement.


channel, ganglionic acetylcholine recep-tor) and CSF findings of elevated protein(greater than 100 mg/dL) or pleocytosis.

Chronic Therapy

Objective improvements that translateinto meaningful gains in functional abili-ties (eg, improvement in memory andthinking, return to work or resumptionof independent living) should promptconsideration of a long-term plan forimmunotherapy because symptomsrelapse in most patients on withdrawalof acute therapies. General guidingprinciples include remission mainte-nance and reduction in corticosteroidor IVIG dependence when possible.The latter objective may be achievedby adding a steroid-sparing inhibitor ofpurine metabolism (Table 4-3), eitheras oral (azathioprine, mycophenolatemofetil, cyclophosphamide, or metho-trexate) or IV (cyclophosphamide)medication. The authors consider aza-thioprine and mycophenolate mofetilsteroid-sparing agents of choice forthis indication, because both havebeen used widely in treating organ-specific autoimmune neurologic dis-eases, such as myasthenia gravis.51,52

Medium- to long-term therapy withcorticosteroids or IVIG may be re-quired in treating patients with auto-immune cognitive disorders, recogniz-ing the multiple and often severe sideeffects of chronic oral corticosteroids(Table 4-3). Potential advantages tolong-term weekly (or less frequentlyadministered) IV corticosteroid ‘‘pulsetherapy’’ over chronic oral corticoste-roids may include a more benign sideeffect profile and safer drug cessation.53,54

In the authors’ practice, we gradu-ally extend the interval between infu-sions of IV corticosteroids or IVIG overa period of 4 to 6 months from weeklyto alternate weeks, every 3 weeks, andthen monthly. At that point, if thepatient is not noting symptomatic

deterioration or improvement coincid-ing with days immediately before orafter an infusion, it is reasonable todiscontinue these therapies and main-tain oral immunosuppressants alone.Faster withdrawal of IV therapy tendsto result in a relapse of cognitive im-pairment, particularly in the absenceof a steroid-sparing immunosuppres-sant agent. Some patients remaindependent on intermittent IV cortico-steroid or IVIG, despite optimizationof oral immunosuppressant therapy.When daily oral prednisone is beingused, a slow reduction from 60-mgprednisone over months is advisable.

Some overlap of treatment with cor-ticosteroid (or IVIG) and a steroid-sparing oral immunosuppressant isrequired, approximately 12 weeks forazathioprine and less for mycopheno-late mofetil (6 to 8 weeks).55 Use ofmycophenolate is limited by expense.Careful monitoring of blood count andliver and renal function is required forpatients treated with either drug, weeklyfor the first month, alternate weekly for2 months, and monthly thereafter.

No data are available to inform theappropriate duration of chronic im-munosuppression in autoimmune de-mentias, whether with corticosteroidsor a steroid-sparing agent. Some pa-tients experience spontaneous remis-sions, and others are dependent lifelongon immunosuppressant medication tomaintain remission. The authors gener-ally initiate a trial of immunosuppres-sant medication withdrawal after 2 to3 years.

The American College of Rheuma-tology Task Force on Osteoporosisrecommends maintaining calcium in-take at 1000 mg/d to 1500 mg/d andvitamin D intake at 800 IU/d (throughdiet or supplements) for patients takingcorticosteroids long term.56 Prophylaxisagainst Pneumocystis carinii pneumo-nia (trimethoprim/sulfamethoxazole, 1double-strength tablet 3 times per week)


96

KEY POINT

A Objective

improvements

should prompt

consideration

of a long-term

plan for

immunotherapy.



also is advised for patients receiving long-term corticosteroids or a purine ana-log.57 Withdrawal of chronic oral cortico-steroids must be done cautiously, withguidance from an endocrinologist orinternist, to avoid emergence of adreno-cortical failure

PROGNOSIS

The prognosis of autoimmune demen-tias varies from sustained completeremission (Case 4-5) with subsequentsuccessful withdrawal of all immuno-therapy to a relapsing-remitting coursemarked by chronic corticosteroid de-pendence. While there are no recog-nized biomarkers predicting outcome,early aggressive treatment with immu-notherapy (within 4 months) seems toimprove prognosis.20

CONCLUSION

The identification of a cognitive disor-der as having an autoimmune patho-genesis, and therefore potentially re-sponsive to immunotherapy, is importantsince otherwise affected patients invari-ably have an unrelenting and often rapiddecline. Comprehensive clinical, neuro-psychological, radiologic, electrophysio-logic, serologic, and CSF evaluationpermits accurate characterization of theneurologic deficits, immunologic abnor-malities, and risk for an underlying can-cer. A favorable response to a prompttrial of immunotherapy further enablesconfident diagnosis and may optimize thepotential for improvements. Chronicityof symptoms and a relapsing course arecommon, but longer-term therapy (al-though requiring frequent monitoring)

97

Case 4-5A 51-year-old female attorney presented with rapid onset of impairedconcentration, poor memory, tremulousness, and episodic righthemianesthesia. The Kokmen Short Test of Mental Status score was27/38, with greatest deficits in attention and recall. She had diffusemyoclonic jerks. MRI head was normal, and EEG revealed mild generalizedslowing. Serologic evaluation revealed thyroid peroxidase antibodies(996 IU/mL; normal value, less than 9.0 IU/mL), and CSF evaluationwas normal. Neuropsychological evaluation documented severeimpairments of information-processing speed, higher-order reasoningand problem solving, naming ability, fluency, calculation, visuospatialfunction, and verbal memory. This global impairment in cognition wasreflected in the diffuse cerebral cortical hypometabolism observed onSPECT imaging. After a 5-day course of IV methylprednisolone thepatient reported subjective cognitive improvements to 90% of normal.This was confirmed objectively by the Kokmen Short Test of MentalStatus (score of 37/38) and by substantial improvements onneuropsychological evaluation. A diagnosis of autoimmune dementiawas made. Because persistent deficits precluded immediate return towork, the patient received IVIG 0.4 g/kg daily for 3 days, followed by0.4 g/kg alternate weeks. Azathioprine also was started (2 mg/kgdaily). After 3 months, the IVIG dosing interval was extended to every3 weeks and later to monthly. IVIG was discontinued after 1 year,but azathioprine was continued. Slow improvement in all clinicaland radiologic abnormalities occurred over a 3-year period after theinitiation of immunotherapy. At last follow-up (4 years after symptomonset), the patient had resumed a successful legal practice.

Comment. This case illustrates that complete resolution of an autoimmunedementia may occur with sustained immunotherapy and careful surveillance.


may permit long-term remission. Treat-ment of autoimmune dementias re-mains empirical. Controlled prospective

studies are needed to determine theoptimum treatments, doses, and dura-tion of therapy.

REFERENCES

1. Geschwind MD, Shu H, Haman A, et al. Rapidly progressive dementia. Ann Neurol2008;64(1):97–108.

2. Kelley BJ, Boeve BF, Josephs KA. Young-onset dementia: demographic and etiologiccharacteristics of 235 patients. Arch Neurol 2008;65(11):1502–1508.

3. Tan KM, Lennon VA, Klein CJ, et al. Clinical spectrum of voltage-gated potassiumchannel autoimmunity. Neurology 2008;70(20):1883–1890.

4. Vincent A, Buckley C, Schott JM, et al. Potassium channel antibody-associatedencephalopathy: a potentially immunotherapy-responsive form of limbic encephalitis.Brain 2004;127(pt 3):701–712.

5. Maselli RA, Agius M, Lee EK, et al. Morvan’s fibrillary chorea. Electrodiagnostic and invitro microelectrode findings. Ann N Y Acad Sci 1998;841:497–500.

6. Spitz M, Ferraz HB, Barsottini OG, Gabbai AA. Progressive encephalomyelitis withrigidity: a paraneoplastic presentation of oat cell carcinoma of the lung: case report.Arq Neuropsiquiatr 2004;62(2b):547–549.

7. Caselli RJ, Boeve BF, Scheithauer BW, et al. Nonvasculitic autoimmune inflammatorymeningoencephalitis (NAIM): a reversible form of encephalopathy. Neurology1999;53(7):1579–1581.

8. Shaw PJ, Walls TJ, Newman PK, et al. Hashimoto’s encephalopathy:a steroid-responsive disorder associated with high anti-thyroid antibodytiters–report of 5 cases. Neurology 1991;41(2[pt 1]):228–233.

9. Castillo P, Woodruff B, Caselli R, et al. Steroid-responsive encephalopathy associatedwith autoimmune thyroiditis. Arch Neurol 2006;63(2):197–202.

10. Susac JO, Egan RA, Rennebohm RM, Lubow M. Susac’s syndrome: 1975–2005microangiopathy/autoimmune endotheliopathy. J Neurol Sci 2007;257(1–2):270–272.

11. Scolding NJ, Joseph F, Kirby PA, et al. Abeta-related angiitis: primary angiitis of thecentral nervous system associated with cerebral amyloid angiopathy. Brain2005;128(pt 3):500–515.

12. Foong J, Rozewicz L, Quaghebeur G, et al. Neuropsychological deficits in multiplesclerosis after acute relapse. J Neurol Neurosurg Psychiatry 1998;64(4):529–532.

13. Hoitsma E, Faber CG, Drent M, Sharma OP. Neurosarcoidosis: a clinical dilemma.Lancet Neurol 2004;3(7):397–407.

14. McKeon A, Marnane M, O’Connell M, et al. Potassium channel antibody associatedencephalopathy presenting with a frontotemporal dementia like syndrome. ArchNeurol 2007;64(10):1528–1530.


98



15. Geschwind MD, Tan KM, Lennon VA, et al. Voltage-gated potassium channelautoimmunity mimicking Creutzfeldt-Jakob disease. Arch Neurol 2008;65(10):1341–1346.

16. Somers EC, Thomas SL, Smeeth L, Hall AJ. Are individuals with an autoimmune diseaseat higher risk of a second autoimmune disorder? Am J Epidemiol 2009;169(6):749–755.

17. Pittock S, Lennon, VA. Paraneoplastic autoimmunity affecting the nervous system.In: Baehring J, Piepmeier JM, eds. Brain tumors: practical guide to diagnosis andtreatment. New Haven, CT: Informa Healthcare, 2006.

18. Graus F, Saiz A, Lai M, et al. Neuronal surface antigen antibodies in limbicencephalitis: clinical-immunologic associations. Neurology 2008;71(12):930–936.

19. Dalmau J, Gleichman AJ, Hughes EG, et al. Anti-NMDA-receptor encephalitis: caseseries and analysis of the effects of antibodies. Lancet Neurol 2008;7(12):1091–1098.

20. Pittock SJ, Yoshikawa H, Ahlskog JE, et al. Glutamic acid decarboxylase autoimmunitywith brainstem, extrapyramidal, and spinal cord dysfunction. Mayo Clin Proc2006;81(9):1207–1214.

21. Vernino S, Lennon VA. Autoantibody profiles and neurological correlations ofthymoma. Clin Cancer Res 2004;10(21):7270–7275.

22. Lai M, Hughes EG, Peng X, et al. AMPA receptor antibodies in limbic encephalitis altersynaptic receptor location. Ann Neurol 2009;65(4):424–434.

23. Lancaster E, Lai M, Peng X, et al. Antibodies to the GABA(B) receptor in limbicencephalitis with seizures: case series and characterisation of the antigen.Lancet Neurol 2009 Dec 2. [Epub ahead of print].

24. Dalmau J, Furneaux HM, Gralla RJ, et al. Detection of the anti-Hu antibody in theserum of patients with small cell lung cancer—a quantitative western blot analysis.Ann Neurol 1990;27(5):544–552.

25. Lucchinetti CF, Kimmel DW, Lennon VA. Paraneoplastic and oncologic profiles ofpatients seropositive for type 1 antineuronal nuclear autoantibodies. Neurology1998;50(3):652–657.

26. Luque FA, Furneaux HM, Ferziger R, et al. Anti-Ri: an antibody associated withparaneoplastic opsoclonus and breast cancer. Ann Neurol 1991;29(3):241–251.

27. Chan KH, Vernino S, Lennon VA. ANNA-3 anti-neuronal nuclear antibody: marker oflung cancer-related autoimmunity. Ann Neurol 2001;50(3):301–311.

28. Sabater L, Titulaer M, Saiz A, et al. SOX1 antibodies are markers of paraneoplasticLambert-Eaton myasthenic syndrome. Neurology 2008;70(12):92492–92498.

29. Vernino S, Lennon VA. New Purkinje cell antibody (PCA-2): marker of lungcancer-related neurological autoimmunity. Ann Neurol 2000;47(3):297–305.

30. Yu Z, Kryzer TJ, Griesmann GE, et al. CRMP-5 neuronal autoantibody: marker of lungcancer and thymoma-related autoimmunity. Ann Neurol 2001;49(2):146–154.

31. Pittock SJ, Lucchinetti CF, Parisi JE, et al. Amphiphysin autoimmunity: paraneoplasticaccompaniments. Ann Neurol 2005;58(1):96–107.


99


32. Rosenfeld MR, Eichen JG, Wade DF, et al. Molecular and clinical diversity inparaneoplastic immunity to Ma proteins. Ann Neurol 2001;50(3):339–348.

33. McKeon A, Lennon VA, Lotze T, et al. CNS aquaporin-4 autoimmunity in children.Neurology 2008;71(2):93–100.

34. Pittock SJ, Lennon VA. Aquaporin-4 autoantibodies in a paraneoplastic context[published erratum appears in Arch Neurol 2008;65(10):1394]. Arch Neurol2008;65(5):629–632.

35. McKeith IG, Dickson DW, Lowe J, et al. Diagnosis and management of dementia withLewy bodies: third report of the DLB Consortium [published erratum appears inNeurology 2005;65(12):1992]. Neurology 2005;65(12):1863–1872.

36. Folstein MF, Folstein SE, McHugh PR. ‘‘Mini-mental state’’: a practical method forgrading the cognitive state of patients for the clinician. J Psychiatr Res 1975;12(3):189–198.

37. Kokmen E, Naessens JM, Offord KP. A short test of mental status: description andpreliminary results. Mayo Clin Proc 1987;62(4):281–288.

38. McKeon A, Ahlskog JE, Britton JA, et al. Reversible extralimbic paraneoplasticencephalopathies with large abnormalities on magnetic resonance images. ArchNeurol 2009;66(2):268–271.

39. Borchers AT, Aoki CA, Naguwa SM, et al. Neuropsychiatric features of systemic lupuserythematosus. Autoimmun Rev 2005;4(6):329–344.

40. Joseph FG, Lammie GA, Scolding NJ. CNS lupus: a study of 41 patients. Neurology2007;69(7):644–654.

41. Weiner SM, Klein R, Berg PA. A longitudinal study of autoantibodies against centralnervous system tissue and gangliosides in connective tissue diseases. Rheumatol Int2000;19(3):83–88.

42. Delalande S, de Seze J, Fauchais AL, et al. Neurologic manifestations in primarySjogren syndrome: a study of 82 patients. Medicine (Baltimore) 2004;83(5):280–291.

43. Pittock SJ, Kryzer TJ, Lennon VA. Paraneoplastic antibodies coexist and predict cancer,not neurological syndrome. Ann Neurol 2004;56(5):715–719.

44. Janssen JC, Godbolt AK, Ioannidis P, et al. The prevalence of oligoclonal bands inthe CSF of patients with primary neurodegenerative dementia. J Neurol 2004;251(2):184–188.

45. Green A, Sanchez-Juan P, Ladogana A, et al. CSF analysis in patients withsporadic CJD and other transmissible spongiform encephalopathies. Eur J Neurol2007;14(2):121–124.

46. McKeon A, Apiwattanakul M, Lachance DH, et al. Positron emissiontomography–computed tomography in paraneoplastic neurologic disorders:systematic analysis and review. Arch Neurol. 2010 Jan 11. [Epub ahead of print]

47. Vernino S, Geschwind M, Boeve B. Autoimmune encephalopathies. Neurologist2007;13(3):140–147.


100



48. Vernino S, O’Neill BP, Marks RS, et al. Immunomodulatory treatment trial forparaneoplastic neurological disorders. Neuro Oncol 2004;6(1):55–62.

49. Hussain NS, Rumbaugh J, Kerr D, et al. Effects of prednisone and plasma exchangeon cognitive impairment in Hashimoto encephalopathy. Neurology 2005;64(1):165–166.

50. Flanagan E, McKeon A, Lennon V, et al. Immunotherapy responsive dementia orencephalopathy: clinical course and predictors of improvements. Ann Neurol2009;66:S41.

51. Palace J, Newsom-Davis J, Lecky B; Myasthenia Gravis Study Group. A randomizeddouble-blind trial of prednisolone alone or with azathioprine in myasthenia gravis.Neurology 1998;50(6):1778–1783.

52. Sanders DB, Siddiqi ZA. Lessons from two trials of mycophenolate mofetil inmyasthenia gravis. Ann N Y Acad Sci 2008;1132:249–253.

53. Frediani B, Falsetti P, Bisogno S, et al. Effects of high dose methylprednisolonepulse therapy on bone mass and biochemical markers of bone metabolism in patientswith active rheumatoid arthritis: a 12-month randomized prospective controlledstudy. J Rheumatol 2004;31(6):1083–1087.

54. Lopate G, Pestronk A, Al-Lozi M. Treatment of chronic inflammatory demyelinatingpolyneuropathy with high-dose intermittent intravenous methylprednisolone. ArchNeurol 2005;62:249–254.

55. Meriggioli MN, Ciafaloni E, Al-Hayk KA, et al. Mycophenolate mofetil for myastheniagravis: an analysis of efficacy, safety, and tolerability. Neurology 2003;61(10):1438–1440.

56. American College of Rheumatology Ad Hoc Committee on Glucocorticoid-InducedOsteoporosis. Recommendations for the prevention and treatment ofglucocorticoid-induced osteoporosis: 2001 update. Arthritis Rheum 2001;44(7):1496–1503.

57. Green H, Paul M, Vidal L, Leibovici L. Prophylaxis for Pneumocystis pneumonia (PCP) innon-HIV immunocompromised patients. Cochrane Database Syst Rev 2007;(3):CD005590.


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immunotherapy- responsive dementias and … · cephalopathy, thyroid autoimmunity, and clinical...

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