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The Neurological Complications of the Herpes Viruses

Joseph R. Berger, MD, FACP, FAAN, FANA Professor

Perelman School of Medicine Department of Neurology University of Pennsylvania

Herpes Viruses

• History – Known since antiquity

– Herodotus coined term “herpes febrilis”

– Genital herpes 1st described by French physician, Astruc (1736)

• 8 known Herpes viruses divided in 3 groups – α-herpes viruses: HSV-1, HSV-2, VZV

– β-herpes viruses: CMV, HHV-6, HHV-7

– γ-Herpes viruses: EBV, KSHV (HHV-8)

• Simian Herpes B can also infect humans

Herpes virus characteristics

• Morphology – DS DNA viruses

– Icosahedral capsule with 162 capsomers

– Surrounded by tegument (amorphous material)

– m.w. = 80-150 X 106

• Genetics – 90 transcriptional units

– 120,000-230,000 base pairs

– Viral replication has nuclear and cytoplasmic phases

– 50% homology between HSV-1 and HSV-2 (most closely related)

– Herpes viruses infecting humans have unique genomic structures

Herpes Virus

1. Attachment via cellular glycoproteins

2. Fusion 3. Preparation of cell (Virion host

shutoff and immediate early gene

products) followed by β or early

peptides (including DNA polymerase)

4. Transportation to nucleopores

and release of DNA into nucleus

5. Transcription and

capsid assembly

6. Envelopment with penetration

of nucleus

7. Transportation to cell surface

via ER and Golgi apparatus

Herpes Virus Replication

Herpes viruses characteristics

• Alpha HHV Family – HSV-1, HSV-2, and VZV

– Establish latency in the PNS

– Peripheral sensory ganglia is the reservoir

– Short reproductive cycle

• Beta HHV Family – CMV, HHV-6, HHV-7

– Establish latency in secretory glands, RES and kidneys

– Slow reproductive cycle

• Gamma HHV Family – EBV and KSHV (HHV-8)

– Establish latency in lymphoid tissue

Herpes Virus Infection of the Peripheral Sensory Ganglia

• Primary infection

• Access to axon endings within mucocutaneous surface

• Retrograde transportation to PSG

• Maintenance of viral genome within the PSG

• Periodic reactivation

• Antegrade transmission to nerve endings and mucocutaneous surface

Herpes Viruses

1. Primary infection involves mucocutaneous surfaces – portal of entry

2. Primary infection generally occurs in the first 3 decades of life; recurrences throughout a lifetime

3. Primary and recurrent disease typically occurs at the same site

4. Recurrent infection rarely spreads beyond anatomic distribution of a single PSG with immunocompetence

Herpes Virus Epidemiology

• Humans only known reservoir

• HSV-1 – >90% of population have HSV-1 Ab by age 50

– ↑ with age

– ↓ with higher socioeconomic status

– Virus typically that carried by mother

• HSV-2 – Varies by population

– Correlates with # of partners, age of sexual debut and other STDs

– U.S.: 25% of white women; 20% of white men; 80% of African American women; 60% of African American men

– Rate of seroconversion is 2-6% per 100 person years

Herpes Virus Epidemiology

• HSV-1 = HSV-2 as cause of genital herpes in some studies

– Decrease exposure to HSV-1 in childhood – Orogenital sex

• HSV-2 can be latent in trigeminal ganglia and may cause oral herpetic lesions – 44 (3.2%) of 1388 subjects had HSV-2 isolated from their mouths

(Wald 2004) – Always asymptomatic – About ½ the frequency of HSV-1 shedding

• 1/3 of primary genital herpes and 60% of primary oral herpetic infections are asymptomatic

HSV-1 Neurological Complications

HSV Encephalitis

• Three possibilities for viral entry into brain – Reactivation of virus from trigeminal ganglion

– In situ reactivation in brain

– Primary infection of CNS

• May arise from primary or recurrent infection – 50% due to primary infection

– 50% due to secondary infection

• only 10% with history of cold sores

• DNA of labial and CNS isolates identical in 50%

• Pathway to limbic structures either via trigeminal ganglia or olfactory nerve

Routes of Viral Entry

HSVE General Features

• Occurs in 1/250,00 to 1/500,000

• Accounts for 10-20% of viral encephalitides

• HSV-1 encephalitis occurs in all ages

– 30% <20 years old but over 6 months

– 50% >50 years old

– Male = female

• Beyond neonatal period – almost always HSV-1

• Rarely observed in immunosuppressed

– Except BMT patients

HSVE Clinical Features

• Fever 92%

• Headache 81%

• Behavioral and personality change 71%

• Seizures 67%

• Hemiparesis 33%

• Memory loss 24%

• Cranial nerve deficits 32%

• Visual field loss 14%

• Papilledema 14%

Whitley JAMA 1982

HSVE Clinical Features

• Generally subacute (< 1 week) in onset

• Absence of fever and headache are rare

• Often preceded by URI symptoms

• Acute psychiatric illness may be clue to dx

• Cortical features predominate

– Personality change, confusion, disorientation

– 1/3 with focal neurological features

HIV-1 Meningitis and NMDA Receptor Encephalitis

• Relapsing HSV-1 encephalitis either1

– True relapse • CSF HSV remains +

• New necrotic lesions on brain MRI

• Responds to acyclovir

– Immune mediated disorder

• Anti-NMDA ab +

– Seizures

• NMDAR Ab+2

• Median age 18.5 years (11-31)

• Prominent psychiatric sxs

• Autonomic instability

• Significant neurological abnormalities

1) Leypoldt F, et al: Neurology 2013; 2) Gable MS, et al: Eur J Clin Microbiol Infect Dis 2009

HSVE Neuroimaging

• Computed tomography – May be normal or subtly abnormal early

– Temporal lobe low density lesions with mass effect

– Hemorrhage highly suggestive of HSVE

– Ill-defined patchy and gyriform CE

• MRI – More sensitive than CT

– Gyral edema on T1WI

– High signal of temporal lobes, insula and cingulate on T2WI and FLAIR

– CE and petechial hemorrhage rare in early disease

HSVE Neuroimaging CT Scan

HSVE Neuroimaging MRI

HSV Encephalitis CSF and other diagnostic studies

• CSF is abnormal in 95% – Moderate pleocytosis (50-100 lymphocytes)

• Up to 3000; PMNs may be seen early

– Red blood cells (40%); Xanthochromia (11%)

– Moderate increase in protein (50-90 mg/dl); 25% normal

– Hypoglycorrhachia is rare

• CSF PCR – Sensitivity 98% and specificity 94%

– False negative typically in first 2 days

• Serodiagnosis

– Serum anti-HSV titer/CSF anti-HSV titer > 20

– CSF antiHSV titer/serum antiHSV titer/CSF alb/serum albumin > 1.9

HSVE Pathology Gross Pathology

Swollen edematous temporal lobe with

multiple petechial hemorrhages

Bilateral cingulate gyri hemorrhages

HSVE Pathology Microscopic

In situ staining for HSV-1

Large eosinophilic nuclear inclusions Perivascular lymphocytic cuffing

Microglia nodules

HSVE Treatment

• Acyclovir 10 mg/kg q 8 h for 2 weeks

– Phosphorylated by viral thymidine kinase

– Inhibits viral DNA polymerase in infected cells

• Demonstration of viral DNA in CSF may dictate an additional 1-2 weeks of ACV Rx

• Other measures

– Prophylactic anticonvulsant Rx

– Respiratory assistance

– ICP monitoring

HSVE Prognosis

HSV-2 Neurological Complications

Case 1: Extremity pain and weakness

• 43 year old female

• 3 months prior to evaluation: – left lower extremity burning and shooting pain

– ↑ weakness in the distal LLE

– Difficulty driving car & climbing steps

• 3 days after onset – back pain and girdle-like sensation of lower abdomen

• Persistent but variable pain for 3 months

• Other sxs present intermittently for 3 weeks

Case 1: Extremity pain and weakness • Consultations

– Neurologists – Neurosurgeons

• EMG of the lower extremity - normal • MRI of the brain – normal • MRIs of C, T, and LS spine - normal • CSF studies:

– WBC 28 (100% lymphs) – Protein & glucose – normal – OCB – negative – IgG and MBP - normal

• VER and SSEP - normal

Case 1: Extremity pain and weakness • PMedHx:

– spontaneous miscarriage

– genital herpes after the birth of her 2nd child

• Family Hx: – unremarkable

• General physical examination was normal

• Neurological examination:

– Cranial nerves were intact

– Motor examination: • Minimal EDL weakness

• DTRs normal

– Sensory examination: • ↓ pinprick and light touch left L5 distribution

• Hyperalgesia in left L5 distribution

Case 1: Extremity pain and weakness

• Laboratory tests: – Routine laboratory tests - normal – CD4, CD8 and CD4/CD8 ratios - normal – HSV 2 Ab titers – 1:256 – Serum antibodies + for EBV and CMV

• LP refused • Treatment: Acyclovir 800 mg 5X day for 14 days • Outcome: Complete resolution of pain and weakness

completely resolved; occasional numbness over left foot • Follow-up:

– 2nd episode of pain, weakness and dysethesias in the same distribution 3 months later

– Resolution with Acyclovir 800 mg 5X day for 14 days – Acyclovir suppressive therapy

• Diagnosis: Elsberg Syndrome

Case #2: Meningoencephalitis with ARN

• 66 year old Cuban American female

• ER Visit

– 10-19-01: body aches, headaches, nausea, fatigue; “Fire ant killer” exposure is raised

– 10-20-01: 4 days of nausea, diffuse aches, chills, ↓ appetite, weakness; T 99.3

– 10-22-01: similar complaints and confused

• PMHx: bipolar disorder, breast cancer, HBP,

hypothyroidism, fibromyalgia, and migraines

• SHx: parrot and parakeet at home

Case #2: Meningoencephalitis with ARN

• PE remarkable for T 100.8

• CXR - left breast implant

• Labs: – ESR 49

– CSF OP 32 and CP 17; clear and colorless; 2 RBCs, 517 WBCs (10% polys; 90% monos); glucose 65; protein 162

– Blood and CSF cultures – negative

– Negative serology: HIV, West Nile, dengue, equine encephalitis, psittacosis

– CT of head - negative

– Consultation with ID and Neurology

– Rocephin, Vancomycin and Doxycycline initiated

Case #2: Meningoencephalitis with ARN

• 10-22-01 hospitalization

• Hospital course: – T max 100o

– No seizures

– No focal neurological findings

– ↓Na+ 2o SIADH

– No MRI performed

– Returns to baseline state by discharge

• 11-08-01 hospital discharge

Case #2: Meningoencephalitis with ARN

• 11-09-01 visit to ER – CC: sudden visual loss – Confused – Pupils slightly reactive

• 11-10-01 visit to Ophthalmology – Pupils 2 mm and unreactive – IOP 30-35 – Light perception only – 1+ cells in anterior chamber – Creamy subretinal exudates with retinal hemorrhages – Dx: Iritis with exudative retinal detachments – Vogt-Harada-Koyanagi syndrome (?)

Iritis and Acute Retinal Necrosis with Hemorrhage

Case #2: Meningoencephalitis with ARN

• 11-13-01 admitted to JMH

– Ophthalmology dx: ARN

– CT scan shows mild atrophy

– Psychiatry consult – AMS 2o to ↓Na+, prednisone and meningitis

– Neurology consult – VHK

– ID consult – Metastatic disease (after reviewing MRI)

– 11-17-01 MRI shows enhancement right inferior temporal lobe and adjacent meninges and small linear enhancing lesion of right frontal lobe

Case #2: Meningoencephalitis with ARN

Case #2: Meningoencephalitis with ARN

Case #2: Meningoencephalitis with ARN

• CSF repeat – 53 WBCs (99% monos) – glucose 112 – protein 120 – IgG/alb index 2.69 (0-0.77) – IgG/alb 0.68 (0.07-0.27) – VDRL negative – Bacterial and fungal cultures – negative – PCR for HSV-1 negative; HSV-2 positive (not known by treating physicians)

• Blood RPR 2+ and TPHA negative • Vasculitis screen ESR – 75; ANA, DS DNA, etc – negative • Ca 19-9 negative • SPEP normal • Lymphocyte subsets - normal

Case #2: Meningoencephalitis with ARN

• Treated with Acyclovir at the suggestion of ophthalmology consult

• ARN 2o to HSV or VZV • CT scan of chest shows thymoma • Discharged after 17 days

– Mental status never fully clears – OD 3/200 and OS HM only – Keratitic precipitates and posterior synechiae

• Thymoma resected on 02-02-02 (invasive) • Radiation therapy to chest after • Review of records reveals diagnosis (2006)

Acute Retinal Necrosis

• Infections: syphilis, Lyme, TB, fungus, CMV, HSV, VZV, rubeola, SSPE, toxoplasmosis, Whipple’s

• Chronic inflammations: sarcoidosis, Vogt-Harada-Koyanagi syndrome, Behçet, SLE

• Multiple Sclerosis

• Malignancies: Reticulum cell sarcoma, lymphoma, metastatic carcinoma

• Miscellaneous disorders: acute posterior pigment epitheliopathy, acute zonal occult outer retinopathy, sympathetic ophthalmia, inflammatory bowel disease

Symptomatic Genital Herpes

• The outbreak of infection is often preceded by prodrome of itching, pain, or an abnormal tingling sensation.

• Prodrome lasts 2 hours to 2 days until blisters develop.

• Blisters heal in approximately 6 to 10 days.

• Symptoms may not resemble those of the primary episode but produce fissures and scrapes in the skin or general genital inflammation.

HSV-2 Neurological Complications

• Neonatal Encephalitis

• Aseptic meningitis (Mollaret’s meningitis)

• Adult meningoencephalitis

• Adult encephalitis

• Acute myelitis

• Myeloradiculitis

• Radiculopathy (Elsberg syndrome) and polyradiculopathy

• Bell’s palsy

• Acute retinal necrosis

Neonatal Herpes Epidemiology

• 90% of neonatal herpes acquired perinatally

– 5-8% congenital

– Rare postnatal acquisition

• 70% born to mothers without sxs or signs

• 30% of NHE is due to HSV-1

• Risk with 1o infection (HSV-1 or -2) is 50%

– ↓ if mother is HSV-1 seropositive

– Risk with HSV-2 seropositivity alone is <1%

Neonatal Herpes Clinical manifestations

• 3 forms – Skin, eyes, and mouth disease – Disseminated disease (mortality 30%; CNS sequelae 20-30%) – Encephalitis (mortality 10%; severe CNS sequelae 40%)

• Skin lesions most commonly recognized – Present in 66% of neonates with encephalitis

• CNS dissemination in 70% – Focal or generalized seizures

• Lab tests often show ↑LFTs and DIC • MRI and CT with diffuse edema early and atrophy, Ca++ and

cystic encephalomalacia late • EEG with slow background and paroxysmal discharges • CSF PCR +: disseminated (93%), encephalitis (76%) and skin,

eye and mouth (24%)

Neonatal Herpes Sequelae following Encephalitis

• Microcephaly 50%

• Seizures 57%

• Ophthalmological disorders 64%

• Cerebral palsy 64%

• Mental retardation 57%

Corey et al Lancet 1988

Aseptic Meningitis

• Primary genital infection – HSV-2:

• 36% of women

• 13% of men

– HSV-1: uncommon

• Recurrent genital infections – Uncommon with either HSV-1 or -2

• May occur in the absence any symptomatic mucocutaneous disorder

Corey et al, Ann Intern Med 1983

Mollaret’s Meningitis with HSV-2 Lancet 1991

Adult HSV-2 Encephalitis and Meningoencephalitis

• Accounts for 6-15% of HSVE

• Typically in immunosuppressed individual

• Less often mesial temporal or orbitofrontal lobes

• MRI may be normal

• Less aggressive with better prognosis

• May present in isolation

– 3 cases in world’s literature

• Recurrent disease described – perhaps when initially

inadequately treated

HSV-2 Brainstem Encephalitis

Tang et al JNNP 2003

HSV-2 Brainstem Encephalitis

Tang et al: JNNSP 2003

HSV-2 Ascending Myelitis

• Likely to be underrecognized

• Typically thoracic or lumbosacral myelopathy

• May be necrotizing with poor prognosis

• May be recurrent

Nakajimi et al: Rinsho Shinkeigaku, 1993

Gobbi et al: Eur Neurol, 2001

Enlargement of conus in a case of

recurrent HSV-2 myelitis in a 70 year old

woman

HSV-2 Radiculopathy

• 40% of sacral DRG have dormant HSV-2

• 5% of 1o genital herpes infection

• Elsberg Syndrome (1931): – urinary retention, CSF pleocytosis and radiculopathy

• Almost always misdiagnosed

• Typically lumbar or sacral nerve root

• Often recurrent

• Seen with other viruses – HSV-1, EBV, VZV, ECHO

HSV-2 Sacral Radiculitis

• 40 year old woman

• lower sacral dermatome sensory loss

• dull pain in the buttock region

• acute urinary retention

Eberhardt et al: Neurology, 2004

Contrast enhanced

MRI with swollen

radicular fibers but

no involvement of

the conus medullaris

Varicella Zoster Virus Neurological Complications

VZV General Features

• High degree of homology with HSV-1

• Cause of chickenpox (varicella)

– >95% 20-29 year olds with Ab to VZV

– 99.6% >40 year olds with Ab to VZV

• Latent in cranial nerves and DRGs

– Cannot be cultured from ganglia (unlike HSV)

– In situ and PCR demonstrate

– Present in neurons and satellite cells

Gilden NEJM 2000

VZV Neurologic Complications

Zoster (Shingles)

• Affects >300,000 in U.S. annually

– Chiefly elderly and immunosuppressed

– Increased risk with varicella < 1 year old

– 8-10 times as common after age 60 years

– Recurrent zoster rare in immunocompetent (<5%)

– Almost all cases of “recurrent zoster” are HSV

Zoster Clinical Features

• Severe sharp, lancinating pain

• Pruritus, dysesthesias, allodynia

• Pain precedes rash by 48-72 hours

• Rash forms over 3-5 days and persists 2-4 weeks

• Radicular or cranial nerve: • Thorax 60%

• Cervical 16%

• Ophthalmic 15%

• Sacral 12.5%

Kumar Ind J Dermatol 2005

Zoster Clinical Features

• Zoster keratitis

• Cranial neuropathies – Optic neuritis

– Ophthalmoplegia with III nerve

– Facial palsy

• Prognosis typically worse than with idiopathic Bell’s palsy

– Ramsey Hunt syndrome (Herpes zoster oticus)

• VII and occasionally VIII nerves

• Tinnitus, deafness, vertigo, N&V, and nystagmus

– Lower cranial nerves rarely

• Zoster paresis

• Sacral zoster with neurogenic bladder

Hutchinson’s sign

Involvement of medial nose Ramsey Hunt syndrome

Zoster Clinical Features

Zoster Treatment

• Antiviral medications

– Famciclovir 500 mg 3 x daily

– Acyclovir 800 mg 5 x daily

– Valtrex 1000 mg 3 x daily

• Antiviral Rx ↓ new lesions and pain

• Antiviral Rx in immunocompetent – efficacy has yet to be demonstrated

• Ophthalmic zoster Rx for >7 days

Postherpetic Neuralgia

• PHN – pain persisting > 6 weeks

• Once pain disappears it does not reappear

• PHN is more common in elderly

– Rare before age 50

– > 60 year olds – 40% affected

• Prevention

– No difference with use of steroids

– Antiviral agents may reduce frequency

– VZV vaccine in persons > 60 year old

Postherpetic Neuralgia Treatment

Gnann NEJM 2002

VZV Myelitis

• Develops 1-2 weeks after rash – More insidious with ↓ immunity

– Long term steroids may predispose

• Paraparesis with sensory level and sphincter dysfunction

• CSF normal or ↑ cells and protein – Cultures for VZV negative

– Demonstration in CSF by PCR

• T2 WI MRI with hyperintense lesion

• Rx with high dose ACV

VZV Large Vessel Encephalitis

• Chiefly in immunocompetent – Most affected > 60 years old

• Clinical features – Acute stroke weeks or months after

contralateral trigeminal zoster

– TIAs and confusion

– Mortality – 25%

• CSF with pleocytosis (<100 mono cells); OCBs; and ↑IgG

• Angiogram with focal and segmental narrowing

• Rx – ACV and corticosteroids

VZV Small Vessel Encephalitis

• Typically in AIDS or other immunocompromised

• Zoster precedes encephalopathy by weeks or months – May develop in absence of antecedent

rash

• Clinical features – Headache, confusion, seizures and focal

deficits

– MRI with WM lesions

– CSF with ↑ monos, normal or ↑ protein

• Rx - ACV

VZV Unusual Neurological Complications

• Immunocompromised hosts, chiefly AIDS

• Clinical manifestations

– Meningoencephalitis

– Ventriculitis with gait abnormality

– Necrotizing vasculitis involving chiefly meninges

Gilden NEJM 2000

Varicella-Zoster Virus in AIDS

• VZV radiculitis common in AIDS and may herald AIDS

• VZV in AIDS brain at autopsy 2-4.4%

• 5 CNS clinico-pathological patterns:

– multifocal encephalitis

– ventriculitis

– acute meningomyelitis with necrotizing vasculitis

– focal necrotizing myelitis

– vasculopathy with cerebral infarction

VZV Encephalitis in AIDS

• Leukoencephalitis – chiefly affects PV area and GW junction

• Subacute encephalopathy – headache, fever, cognitive change,

lethargy, seizures, and focal findings

• Evolves over weeks – occasionally acute or over many months

• CT/MRI limited value

• CSF PCR for VZV helpful

VZV Myelitis

• Temporal association with cutaneous eruption

– may occur months after eruption or myelitis may precede eruption

• Acute or subacute evolution of myelitis

• Polyradicular features may mimic CMV

• Extensive hemorrhagic necrotizing myelitis

with vasculitis and thrombosis in DRG

VZV cerebral vasculopathy

• May involve large or small vessels

• may be inflammatory or bland

• often preceded by zoster ophthalmicus

• interval up to one year

• associated VZV encephalitis or meningomyelitis not uncommon

Leptomeningeal artery with intimal

fibrosis and almost complete

luminal occlusion.

CNS VZV Treatment in AIDS

• no randomized prospective clinical trials

• progression of encephalitis and myelitis despite treatment with ACV or GCV – ~50% will recover (de la Blanchardiere 2000)

• famciclovir anecdotally helpful

• high doses for indefinite periods of time

• foscarnet recommended for ACV-resistant cutaneous zoster, however, no evidence of CNS efficacy

• prophylactic Rx with ACV (1600-4000 mg/d) when CD4<50 recommended by some (Leautez 1999)

• vidarabine fails to prevent VZV encephalitis

Cytomegalovirus • Serologic evidence of infection in 90% of AIDS patients

• Molecular techniques frequently reveal CMV Ag or DNA

– > of AIDS brains

– 27% of neuromuscular tissues

• 19% with AIDS for <3 months

• 46% with AIDS >2 years

• Broad spectrum of neurologic disorders

– necrotizing ventriculitis

– focal necrotizing encephalitis

– CNS vasculitis

– focal necrotizing myelitis

– CMV polyradiculomyelitis

– multifocal neuritis and arteritis

Cytomegalovirus Encephalitis

• Virtually all with systemic evidence of infection

• Impaired cognition and sensorium

• Variable motor abnormalities including weakness and ataxia

• Ventriculitis associated with cranial neuropathies, ocular motor abnormalities, nystagmus, and progressive ventricular enlargement

• Combined neurologic deficits, e.g., myelitis and peripheral

neuropathy not uncommon

Cytomegalovirus Neurological Complications

Cytomegalovirus Systemic Manifestations

CMV Pneumonia Hemorrhagic CMV retinitis

Cytomegalovirus Encephalitis

Corpus callosum and frontal

horns of both lateral ventricules

are necrotic

Microglial nodule with cytomegalic cell

(Nissl stain)

CMV Ventriculoencephalitis

Contrast CT and MRI with ventricular enhancement. Non-specific as

may be seen with toxoplasmosis, cryptococcus, and lymphoma.

CMV Ventriculoencephalitis

Characteristic intranuclear CMV inclusion bodies in the

epithelial cells of the choroid plexus

Focal Necrotizing CMV Encephalitis

Necrotic focus with hemorrhage within the left putamen

CMV Polyradiculomyelitis

• Lower extremity and sacral paresthesiaes

• Rapidly progressive paraparesis

• Areflexia

• Ascending sensory loss

• Occasional thoracic sensory level

• Urinary retention

• CSF polymorphonuclear pleocytosis

• MRI with Gd enhancement of cauda equina

• CMV in blood, urine, and CSF

CMV polyradiculomyelitis MRI Findings

Contrast

enhancement of

lumbar spinal cord

Contrast enhancement of spinal

nerve roots of cauda equina

CMV polyradiculomyelitis

Anterior horn of lumbar

cord. Marked central

chromatolysis.

Spinal ganglia. Inflammatory

infiltrate and neuronophagia

with ‘nodule of Nageotte’ and

CMV inclusion (arrow).

CMV Treatment in HIV

• Ganciclovir (9-1,3,-dihydroxy-2-propoxymethyl)-guanine)

– acyclic nucleoside requiring intracellular phosphorylation

– first phosphorylation step is dependent on viral phospho-transferase and accumulation within infected cells

– demonstrated efficacy for retinitis and gastroenteritis

– reaches mean CSF concentration of 40% of plasma

– equivalent of plaque-forming unit reduction of 50% (ED50) at common current doses of 2.5 mg/kg q12 h

– hematologic toxicity - neutropenia and thrombocytopenia

CMV Treatment in HIV

• Foscarnet (trisodium phosphonoformate)

– effects CMV DNA polymerase without requiring phosphorylation

– established effective for CMV retinitis

– CSF penetration varies between 27% of plasma concentration to

66% with prolonged therapy

– CSF levels above ED50 for CMV at 90 mg/kg q12 h

– renal toxicity most significant

– seizures and paresthesias

CMV Treatment in HIV Caveats for the Neurological Disease

• Anecdotal evidence only for CNS and PNS disease

• Response may be very slow, particularly for CMV polyradiculomyelopathy

• Emergence of resistance CMV strains observed with treatment failure

• Addition of foscarnet to ganciclovir valuable

• relapse common

• Duration of therapy remains uncertain

Epstein-Barr Virus Neurological Complications

Epstein-Barr Virus

• Infects B and T cells of > 90% of population before adulthood

• Replicates in oropharynx

• Transmitted by oral secretions

• Acute infection results in transient viremia

• EBV associated with variety of tumors – nasopharyngeal carcinoma

– Burkitt’s lymphoma

– Hodgkin’s disease

– LPD in immunocompromised

EBV Neurological Disorders

– Psychiatric manifestations and Alice in Wonderland syndrome

– Acute hemiplegia

– PCNSL

– Aseptic meningitis

– Encephalitis

– GBS

– Cranial nerve palsies

– Transverse myelitis

– Cerebellar ataxia

Neurological disease develops in 5-8% of

infectious mononucleosis cases

Spectrum of Neurological Disorders

EBV-Associated PCNSL

• PCNSL accounts for 15% of non-Hodgkins lymphoma in HIV

• Majority are EBV related (85-94%)

– Ineffective immune regulation of EBV

– Oncogenic protein expression

– Loss of apoptosis

– Increased proliferation of lymphocytes

• Role of antiviral for EBV remains to be established

Brandsma and Bromberg: Hdbk Clin Neurol 2018

HHV-6 Neurological Complications

HHV-6

• Etiology of roseola

• May directly invade the CNS

• HHV-6 detected in CSF of febrile seizure patients

• CSF PCR or paired serum and CSF IgG to HHV-6

• Complications include: – Encephalitis after BMT

– Limbic encephalitis

• Implicated in pathogenesis of MS – Found in only a minority of MS patients

– ↑ HHV-6 Ab found with other illnesses

• Treatment with foscarnet or ganciclovir

Roseola (Sixth Disease)

HHV – 6

Noguchi et al: AJNR 2006

Humanity has but three great enemies; fever, famine and war; of

these by far the greatest, by far the

most terrible, is fever

Sir William Osler

Chair of Clinical Medicine at Penn 1885

1849-1919