Journal of NeuroVirology

, Volume 22, Issue 6, pp 876–879 | Cite as

Normonatremic osmotic demyelination in the setting of acquired immune deficiency syndrome and malnutrition: case report and literature review

  • James E. Siegler
  • Amber R. Wang
  • Joshua D. Vanderwerf
Case Report

Abstract

In this report, we present the case of a 43-year-old woman with AIDS, disseminated aspergillosis, and malnutrition who developed osmotic demyelination syndrome. AIDS-related osmotic demyelination has only been documented in a handful of cases to date, and it appears independent of the classic mechanism of rapid correction of hyponatremia. In this manuscript, we review the six prior cases of osmotic demyelination in AIDS patients and compare their circumstances to that of our own patient. It appears that complications of malnutrition, possibly related to depletion of organic osmolytes in the central nervous system, may place AIDS patients at greater risk of osmotic demyelination. These, and other proposed mechanisms, deserve further inquiry.

Keywords

Osmotic demyelination Posterior reversible encephalopathy Acquired immune deficiency syndrome Aspergillosis Status epilepticus 

Case report

A 43-year-old Liberian woman with a recent diagnosis of human immunodeficiency virus (HIV) type 1/acquired immune deficiency syndrome (AIDS) and tuberculous meningitis was admitted to an internal medicine service for chronic secretory diarrhea.

Four months prior to her current admission, the patient was diagnosed with HIV/AIDS in the setting of fevers, 100-lb. weight loss, and headache. Her serum CD4+ cell count was 188 cells/μL, HIV-1 ribonucleic acid quantitation was 214,779 copies/mL, and pre-albumin was <3.0 mg/dL (reference: 18–38 mg/dL). A lumbar puncture was notable for a mild lymphocytic pleocytosis (10 cells/μL, 93 % lymphocytes, 0 % malignant cells) and slight protein elevation to 50 mg/dL but normal glucose (60 mg/dL in the CSF, 94 mg/dL in the serum). Testing for HSV, VZV, syphilis, and computed tomography of the chest/abdomen/pelvis was unremarkable. Serum tuberculosis antigens were mildly elevated (0.80 IU/mL, reference ≤0.34 IU/mL), but three sets of sputum cultures did not grow acid-fast bacilli. She was started on sulfamethoxazole-trimethoprim and combination therapy for tuberculosis (rifabutin, isoniazid, pyrazinamide, and ethambutol with pyridoxine and cyanocobalamin). The patient developed a subacute oculomotor nerve palsy 1 month later in the setting of tuberculous meningitis. Highly active anti-retroviral therapy (HAART) was delayed until improvement in the third nerve palsy.

Her CD4+ cells reconstituted to 105 cells/μL by day 5 of hospitalization with continuation of HAART. The serum HIV-1 quantitation had improved to <20 copies/mL by day 49. Her neurologic examination at the time of admission was non-focal. Diagnostic testing was remarkable for serum and sputum cytopathology revealing Aspergillus species, for which she received voriconazole. She waxed and waned over the following weeks due to disseminated aspergillosis and recurrent sepsis.

On day 48, she developed acute rightward eye deviation with generalized tonic-clonic movements of all four extremities. She was treated with intravenous lorazepam and levetiracetam and intubated for hypercarbic respiratory failure. She was not hypertensive. Brain MRI demonstrated findings consistent with posterior reversible encephalopathy (PRES) and a new left occipital lobe infarction (Fig. 1). EEG confirmed non-convulsive status epilepticus. Valproic acid, lacosamide, and a midazolam infusion were initiated. Repeat lumbar puncture demonstrated a protein of 104 mg/dL, glucose 38 mg/dL, 1 white blood cell, and negative testing for cryptococcal antigen, gram stain and culture, Epstein Barr virus, JC virus, and toxoplasma. Serum chemistries are summarized in Supplementary Fig. 1. Osmolality was never assessed, but the pre-albumin peaked at 7.9 mg/dL.
Fig. 1

Brain magnetic resonance imaging. a Unremarkable non-enhanced FLAIR study at the time of HIV diagnosis (4 months prior to admission). b Non-enhanced FLAIR 1 month after HIV diagnosis when new third nerve palsy diagnosed. New area of pontine signal change without restricted diffusion. No meningeal enhancement noted on T1 post-gadolinium sequence. Patient was clinically diagnosed with tuberculous meningitis. c Gadolinium-enhanced FLAIR on hospital day 48. Bilateral hyperattenuating cerebellar and pontine signal change concerning for PRES. d Gadolinium-enhanced FLAIR on hospital day 65. Interval resolution of cerebellar signal change with new development of central pontine FLAIR change concerning for osmotic demyelination. FLAIR denotes fluid attenuated inversion recovery, HIV human immunodeficiency, PRES posterior reversible encephalopathy syndrome

The status epilepticus resolved within 24 h, and she was weaned slowly off midazolam over the next 2 weeks. Her exam at that time was notable for spontaneous eye blinking and tracking, vertical skew with a right gaze preference, intact corneal response, and preserved gag reflex, but flaccid extremities and no response to noxious stimulation. A brain MRI for prognostication on day 65 demonstrated interval resolution of PRES, but there was new signal abnormality in the pons concerning for osmotic demyelination (Fig. 1). Given her poor prognosis, the family desired comfort measures only. She expired on hospital day 68, and the family consented to autopsy. Histopathology confirmed pontine osmotic demyelination (Fig. 2).
Fig. 2

Histopathology demonstrating osmotic demyelination. a Basis pontis showing a well-circumscribed and completely demyelinated area with symmetric involvement both right and left of midline. Note that the pontine neurons within the area are still recognizable (Luxol fast blue). b Demyelinated areas are characterized by large numbers of foamy macrophages. These can be emphasized by staining with CD68

Discussion

Adams first described central pontine myelinolysis in alcoholics and malnourished patients in 1959 (Adams et al. 1959). It would eventually become clear that almost all cases of ODS occurred in the setting of chronic illness. Reported cases have occurred concomitantly with alcoholism, malnutrition, liver disease, cancer, burns, renal failure, AIDs, infections, and other conditions (Kleinschmidt-Demasters et al. 2006, Norenberg 2010). Over the years, reported cases of ODS occurring in normonatremic patients suggest that correction of hyponatremia is not the sole mechanism of ODS (Kilinç et al. 2002, Landais 2014, Bernsen and Prick 1999). The current hypothesis maintains that rapid change to a hyperosmolar state, depleted intracellular organic osmolytes, breakdown of the blood-brain barrier, oligodendrocyte apoptosis, and inflammation all may play a role in ODS (Norenberg 2010). Our patient had no evidence of electrolyte derangements or a hyperosmolar state. Although our patient was malnourished, there was no history of alcoholism or liver dysfunction.

To date, only six other cases of ODS occurring in normonatremic AIDS patients have been reported (Table 1) (Apoola et al. 2003, Carrington et al. 2015, Holmes et al. 1992, Miller et al. 1998, Odero et al. 2009). These patients were documented as having serious opportunistic infections and concomitant malignancies as well as hypoalbuminemia, as in the case of the patient presented in this report. Based on this simple review, ODS appears to bear a significant relationship with AIDS-related malnutrition independent of the degree of immune dysfunction (by CD4+ count), alcohol abuse, and sepsis.
Table 1

Summary of reported cases of ODS in the setting of normonatremic AIDS patients

Case

Age

Sex

CD4+ count (cells/μL)

Alcohol abuse

Hyponatremia (admission serum sodium <135 mg/dL)

Rapid correction of hyponatremia

Malnourished

Sepsis

Histopathologic confirmation of ODS

1 (Miller et al. 1998)

36

M

70

No

No

Yes

Yes

Yes

2 (Miller et al. 1998)

35

M

Yes

No

Yes

Yes

Yes

3 (Holmes et al. 1992)

49

M

No

No

Yes

No

Yes

4 (Apoola et al. 2003)

32

F

140

No

No

Yes

Yes

No

5 (Odero et al. 2009)

38

F

14

No

No

No

No

No

6 (Carrington et al. 2015)

53

M

54

No

Yes*

No

Yes

No

No

Our patient

43

F

105

No

No

Yes

Yes

Yes

List of cases excludes the two histopathologic cases reported in the series by Kure et al. (1991)

ODS osmotic demyelinating syndrome, AIDS acquired immune deficiency syndrome

*Admission serum sodium 129 mg/dL

However, three of these previously reported cases do not provide histopathologic confirmation of ODS, and only one of the remaining three documents a CD4+ cell count. This makes generalization of our findings difficult. It is unclear why ODS is a rare complication of AIDs independent of serum osmolality changes. Some investigators have speculated it may be related to depletion of organic osmolytes (amino acids, creatine, and citric acid cycle metabolites) and blood-brain barrier dysfunction in the setting of severe malnutrition (Norenberg 2010). Why this occurs spontaneously in the setting of chronic—but critical—illness, as in the case of our patient with PRES and status epilepticus, remains a mystery. It is likely that traditional mechanisms such as chronic hyponatremia and rapid restoration of serum osmolality do not contribute to the development of ODS in AIDS patients; however, this is unsubstantiated. Chronic HIV infection (to the point of developing AIDS) of the central nervous system may lead to functional disruption of the blood-brain barrier (Ivey et al. 2009) and lower the threshold for adverse neurologic events such as ODS and progressive multifocal leukoencephalopathy. One could speculate that the development of PRES in our patient, likely related to sepsis, status epilepticus, HIV, or a combination thereof, is one such manifestation of early blood-brain barrier breakdown. Immune reconstitution syndrome (IRIS) in the setting of anti-retroviral therapy was also considered as a causative mechanism in this case of ODS, but there were no other systemic features of IRIS, and IRIS has not been reported to our knowledge in any case of ODS. Furthermore, entities such as PRES and IRIS were not unifying features across any of the six other reported cases of HIV-associated ODS. Or it may be that complications of HIV, such as malnutrition (a feature shared by chronic alcoholic and AIDs patients alike) and the chronic stress response, may increase the patient’s susceptibility to ODS in a manner independent of viral injury or immune reconstitution. These mechanisms warrant further research in order for clinicians to prevent this incompletely understood, but fatal, consequence of critically ill patients with AIDS.

Notes

Compliance with ethical standards

Study funding

None.

Conflict of interest

The authors declare that they have no conflict of interest.

Supplementary material

13365_2016_463_MOESM1_ESM.png (111 kb)
Supplementary Figure 1Serum laboratory results in the 7 days preceding and 3 days following MRI diagnosis of osmotic demyelination. Serum osmolality was not assessed. MRI denotes magnetic resonance imaging, HD hospital day. (PNG 111 kb)

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Copyright information

© Journal of NeuroVirology, Inc. 2016

Authors and Affiliations

  • James E. Siegler
    • 1
  • Amber R. Wang
    • 2
  • Joshua D. Vanderwerf
    • 1
  1. 1.Department of NeurologyHospital of the University of PennsylvaniaPhiladelphiaUSA
  2. 2.Department of Pathology and Laboratory MedicineHospital of the University of PennsylvaniaPhiladelphiaUSA

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