| Article Access Statistics|
| Viewed||536 |
| Printed||16 |
| Emailed||0 |
| PDF Downloaded||27 |
| Comments ||[Add] |
Click on image for details.
|LETTERS TO EDITOR
|Year : 2019 | Volume
| Issue : 1 | Page : 261-264
Knowing the unknown – CD8 encephalitis: A novel form of HIV-associated neurocognitive disorder
Sumeet P Mirgh1, Vikas A Mishra2, Rishit K Harbada3, Jehangir S Sorabjee4
1 Department of Neurology, Bombay Hospital Institute of Medical Sciences, Mumbai, Maharashtra, India and AIIMS, New Delhi, India
2 Bombay Hospital Institute of Medical Sciences, Mumbai, Maharashtra; GSVM Medical College, Kanpur, Uttar Pradesh, India
3 Bombay Hospital Institute of Medical Sciences, Mumbai, Maharashtra, India
4 Department of Medicine, Bombay Hospital Institute of Medical, Sciences, Mumbai, Maharashtra, India
|Date of Web Publication||7-Mar-2019|
Dr. Sumeet P Mirgh
401, Jai Gurudev C.H.S., Plot no-6, Sector-1, Sanpada, Navi Mumbai - 400 705, Maharashtra
Source of Support: None, Conflict of Interest: None
|How to cite this article:|
Mirgh SP, Mishra VA, Harbada RK, Sorabjee JS. Knowing the unknown – CD8 encephalitis: A novel form of HIV-associated neurocognitive disorder. Neurol India 2019;67:261-4
|How to cite this URL:|
Mirgh SP, Mishra VA, Harbada RK, Sorabjee JS. Knowing the unknown – CD8 encephalitis: A novel form of HIV-associated neurocognitive disorder. Neurol India [serial online] 2019 [cited 2019 Aug 22];67:261-4. Available from: http://www.neurologyindia.com/text.asp?2019/67/1/261/253630
Spectrum of human immunodeficiency virus (HIV)-associated neurocognitive disorders (HAND) varies from asymptomatic neurocognitive impairment to minor neurocognitive dysfunction to HIV-associated dementia. It is the most common central nervous system (CNS) complication of HIV. Cluster of differentiation-8 (CD8) encephalitis is a new form of CNS immune reconstitution inflammatory syndrome (IRIS) characterized by CD8+ Tcell infiltration into the brain without high viral burden in the CNS or typical IRIS presentation. CD8+ cells in the cerebrospinal fluid (CSF) and post-gadolinium T1 perivascular contrast enhancement are diagnostic. Very few cases have been reported.,,,,
To the best of our knowledge, no case has been reported from India.
A 55-year old right-handed businessman, a known case of retroviral disease, presented in July 2014 with a 3-month history of increased sleepiness, episodic involuntary facial movements, memory disturbance, and slurring of speech. He was diagnosed with HIV-1 10 years back and started on an AZT/3TC/NVP regimen [AZT (zidovudine), 3TC (lamivudine), NVP (nevirapine)]. Four years later, he developed pneumocystis-carinii pneumonia wherein his CD4 counts decreased >50% and viral load increased to >7,00,000 copies/ml. Hence, he was shifted to second-line antiretroviral therapy (ART)–TDF/FTC/ATV(r) (tenofovir, emtricitabine, boosted atazanavir). He was virologically well suppressed on the second regimen for 5 years. On admission, his Mini-Mental Status Examination (MMSE) score was 19 with impaired recall and calculation. CNS examination revealed a bilateral upper motor neuron facial nerve involvement, a prominent jaw jerk, grade 4 power in all four limbs with spasticity, hyperreflexia, bilateral ankle clonus, and bilateral Babinski's sign. The patient had spastic dysarthria with intermittent facial tics.
He was investigated as shown in [Table 1], [Table 2], [Table 3] and [Figure 1], [Figure 2], [Figure 3], [Figure 4] below. In view of the magnetic resonance imaging findings and a stable CD4 count, special CSF investigations were done, as shown in [Table 4]. Investigations revealed a significantly elevated CD8+ T-cell count in the CSF along with elevated CNS HIV viral load in the presence of suppressed plasma viral load. CNS immune dysregulation was thus evidenced by disproportionate presence of CD8+ T-cells in the CSF. Hence, he was given intravenous pulse methylprednisolone 500 mg for 5 days and ART regimen modified to ABC/3TC/DRV (r) combination (abacavir, 3TC, boosted darunavir) for better CNS penetration. His facial tics and drowsiness improved within 2 weeks, followed by gradual improvement in memory (MMSE 26) and spasticity over the next 8 weeks. At 2 years of follow-up, he is stable without any neurological deterioration.
|Figure 1: T2-weighted axial image showing hyperintensities in bilateral periventricular white matter. Arrows show that the periventricular hyperintensities are more prominent over the frontal horns (front vertical arrows)|
Click here to view
|Figure 2: T2 FLAIR axial image. Arrow in the right hemisphere showing asymmetric hyperintensity in the right periventricular and right fronto-parietal white matter. In the left hemisphere, the hyperintensity in high parietal white matter is indicated by the vertical arrow and the hyperintensity in the left parieto-occipital junction indicated by the horizontal arrow|
Click here to view
|Figure 3: Post-gadolinium contrast T1-weighted image showing enhancement perpendicular to ventricular margins (arrows indicating enhancement better appreciated on the left side) most likely representing perivascular enhancement|
Click here to view
|Figure 4: DWI (diffusion-weighted images) showing periventricular diffusion restriction|
Click here to view
CD8 encephalitis is characterized by a diffuse but predominantly perivascular infiltration of polyclonal CD8+ lymphocytes. Four causes have been identified: trivial infection in well-controlled patients, CNS IRIS, virological escape, and highly activated anti-retroviral therapy (HAART) interruption. Mascolini's group of 14 HIV patients had a median age of 41 years, HIV infection for 10 years duration, median CD4 of 493, and median plasma viral load 117 copies. The condition presented subacutely in almost 50% patients, which included epilepsy, headache, coma, dizziness, confusion, dementia, mild memory disorders, neurologic deficit, and “mood troubles.” Our patient was a pentagenerian living with HIV for more than a decade and a median CD4 of 460. He presented subacutely with memory disturbance and bipyramidal signs. The pyramidal signs were unique as it has not yet been reported in literature. These symptoms usually occur during immune reconstitution (early in the course of therapy) or during treatment interruption  unexpectedly striking clinically and immunologically stable patients. Our patient similarly presented when he was immunovirologically stable [Table 1] on second-line ART for 5 years.
ART drugs have a CNS penetration effectiveness (CPE) score. As per studies, regimens with a high CPE score are essential to achieve CSF HIV-1 ribose nucleic acid (RNA) suppression,,, and it is a better predictor of treatment failure.,
A close differential diagnosis is acute disseminated encephalomyelitis (ADEM). In CD8 encephalitis, T2- fluid attenuated inversion recovery sequence (FLAIR) hyperintensities are more diffuse and poorly delineated in contrast to the large and multiple lesions seen in ADEM, but the principal differences are the gadolinium-enhanced lesions. In CD8 encephalitis, they are thinner than 2mm and follow perivascular spaces with a linear/punctuate shape amidst the FLAIR hyperintensities, whereas in ADEM, the enhancement is peripheral with a ring/incomplete ring-shaped formation. Lesions in HIV encephalitis, in contrast to CD8 encephalitis, are typically located periventricularly, in the basal ganglia, cerebellum, or brainstem, and there may also be atrophy. Progressive multifocal encephalopathy (PML) exhibits multifocal white matter lesions with features of demyelination which spare the cortical ribbon. It is also characterized by a hyperintense signal on T2WI, dark signal on T1WI, no edema/mass effect, and a rare enhancement with gadolinium (contrast to CD8 encephalitis). Interestingly, some experts hypothesize that PML is due to CD8+ T-cell lymphocytopenia, as its presence in the CNS compartment is protective against JC-virus. Our case had bilateral hyperintensities on T2-FLAIR and perivascular enhancement on post-contrast sequence, which were diagnostic.
CSF pleocytosis in these patients comprised >90% lymphocytes, which were mainly CD8+ lymphocytes expressing the CCR5 phenotype. The mean CSF HIV viral load was 5949 copies/ml in one study  and 2236 copies/ml in the second  without any role of blood CD8 count. Our case had a CSF HIV viral load of 11,157copies/ml and disproportionately increased CSF CD8 cells.
In certain cases, the inflammation after HIV infection may overshoot its objective.
Corticosteroids block this phenomenon. One study showed a mean survival time of 8 years, whereas the other reported considerable improvement with steroids in one-third of patients over a median follow-up of 4 years. Patients were treated with intravenous methylprednisolone followed by a tapering dose of prednisone (1 mg/kg for 2 months followed by a reduction of 5mg every 2 weeks) for a median period of 6 months as proposed in ADEM. Our patient responded to methylprednisolone and is stable on follow-up despite no long-term oral steroids being administered.
The triad of subacute diffuse severe encephalitis, CD8+ T-cells in CSF, and a diffuse leukoencephalopathy with restricted diffusion and perivascular contrast enhancement on imaging has been suggested as the diagnostic triad for CD8 encephalitis. In the absence of CSF flowcytometry for diagnosis in resource-limited settings, a post-contrast T1 spin echo-sequence with magnetization transfer should be done in a patient with suppressed plasma viral load with unexplained cognitive decline. Clinicians should be cognizant of this entity as it is treatable by corticosteroids and ART modification.
Financial support and sponsorship
Conflicts of interest
There are no conflicts of interest.
| » References|| |
Smurzynski M, Wu K, Letendre S, Robertson K, Bosch RJ, Clifford DB, et al
. Effects of central nervous system antiretroviral penetration on cognitive functioning in the ALLRT cohort. AIDS 2011;25:357-65.
Langford D, Letendre S. Severe HIV-associated CD8+
T-cell encephalitis: Is it the tip of the iceberg? Clin Infect Dis 2013;57:109-11.
Lescure FX, Moulignier A, Savatovsky J, Amiel C, Carcelain G, Molina JM, et al
. CD8 encephalitis in HIV-infected patients receiving cART: A treatable entity. Clin Infect Dis 2013;57:101-8.
Mascolini M. New, deadly, but rare encephalitis described in 14 French HIV patients. XVIII International AIDS Conference, Vienna, July 18-23, 2010.
Cusini A, Vernazza PL, Yerly S, Decosterd LA, Ledergerber B, Fux CA, et al
. Swiss HIV Cohort Study. Higher CNS penetration-effectiveness of long-term combination antiretroviral therapy is associated with better HIV-1 viral suppression in cerebrospinal fluid. J Acquir Immune Defic Syndr 2013;62:28-35.
Imaz A, Cayuela N, Niubó J, Tiraboschi JM, Izquierdo C, Cabellos C, et al
. Short communication: Focal encephalitis related to viral escape and resistance emergence in cerebrospinal fluid in a patient on lopinavir/ritonavir monotherapy with plasma HIV-1 RNA suppression. AIDS Res Hum Retroviruses 2014;30:984-7.
Moulignier A, Savatovsky J, Polivka M, Boutboul D, Depaz R, Lescure FX. CD8 T lymphocytes encephalitis mimicking brain tumor in HIV-1 infection. J Neurovirol 2013;19:606-9.
Letendre S. Central nervous system complications in HIV disease: HIV-associated neurocognitive disorder. Top Antivir Med 2011;19:137-42.
Miller RF, Isaacson PG, Hall-Craggs M, Lucas S, Gray F, Scaravilli F et al
. Cerebral CD8+ lymphocytosis following HAART-induced immune restoration. Acta Neuropathologica 2004;108:17-23.
Ndhlovu LC, Umaki T, Chew GM, Chow DC, Agsalda M, Kallianpur KJ, et al
. Treatment intensification with maraviroc (CCR5 antagonist) leads to declines in CD16-expressing monocytes in cART-suppressed chronic HIV-infected subjects and is associated with improvements in neurocognitive test performance: Implications for HIV-associated neurocognitive disease (HAND). J Neurovirol 2014;20:571-82.
Helleberg M, Kirk O. Encephalitis in primary HIV infection: Challenges in diagnosis and treatment. Int J STD AIDS 2013;24:489-93.
Le LT, Spudich SS. HIV-associated neurologic disorders and central nervous system opportunistic infections in HIV. Semin Neurol. 2016;36:373-81.
McGuire JL, Fridman V, Wuthrich C, Koralnik IJ, Jacob D. Progressive multifocal leukoencephalopathy associated with isolated CD8+ T-lymphocyte deficiency mimicking tumefactive MS. J Neurovirol. 2011;17:500-3.
[Figure 1], [Figure 2], [Figure 3], [Figure 4]
[Table 1], [Table 2], [Table 3], [Table 4]