A Systematic Review of Sodium Disorders in HHV-6 Encephalitis

Sodium Disorders in HHV-6 Encephalitis

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A Systematic Review of Sodium Disorders in HHV-6 Encephalitis NikolasC. Victoria , TuanL. Phan , KrishnaA. Agarwal M.D. PII: DOI: Reference:

S1083-8791(20)30056-2 https://doi.org/10.1016/j.bbmt.2020.01.023 YBBMT 55916

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Biology of Blood and Marrow Transplantation

Received date: Accepted date:

13 January 2020 28 January 2020

Please cite this article as: NikolasC. Victoria , TuanL. Phan , KrishnaA. Agarwal M.D. , A Systematic Review of Sodium Disorders in HHV-6 Encephalitis, Biology of Blood and Marrow Transplantation (2020), doi: https://doi.org/10.1016/j.bbmt.2020.01.023

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Highlights



Abnormal sodium levels prior to or at onset of HHV-6 encephalitis in 94% of cases.



Hyponatremia made up 85% of cases of sodium imbalance with HHV-6 encephalitis.



Hyponatremia may be an early indicator of HHV-6 encephalitis, especially after HCT.

A Systematic Review of Sodium Disorders in HHV-6 Encephalitis Short Title: Sodium Disorders in HHV-6 Encephalitis Nikolas C. Victoria1, Tuan L. Phan1,2, Krishna A. Agarwal3*

Affiliations: 1 HHV-6

Foundation, Santa Barbara, CA, USA

2 Department

of Microbiology and Immunology, Tulane University School of Medicine, New

Orleans, LA 3 Beth

Israel Deaconess Medical Center, Harvard Medical School, Boston, MA, USA

*Corresponding author: Krishna A. Agarwal, M.D. E-mail address: [email protected]

Keywords hyponatremia, hypernatremia, SIADH, HHV-6, encephalitis Abstract HHV-6 encephalitis has a high mortality rate. Among those who survive, ~80% develop some type of permanent neurological disorder. Early diagnosis and treatment may help prevent long-term sequelae. There have been several case reports, as well as retrospective and prospective studies associating HHV-6 encephalitis with some form of sodium imbalance, i.e. hyponatremia and hypernatremia. But the exact frequency post-HCT is unknown, ranging from 30-100%. We performed a systematic review of the literature and found 34 cases of HHV-6 encephalitis reported in conjunction with sodium imbalance which documented the timing of that imbalance relative to the onset of encephalitis.

Sodium imbalance occurred prior to or at the onset of encephalitis in all but 2 cases (94%). This supports previous suggestions that sodium imbalance could be considered an early indicator for the potential development or presence of HHV-6 encephalitis in at-risk patient populations. Introduction HHV-6 is the collective name of two distinct viral species, HHV-6A and HHV-6B, both members of the subfamily betaherpesvirinae, which also includes cytomegalovirus (CMV) and HHV-7. Seropositivity to HHV-6 is greater than 95% in adults in developed countries1 with nearly 80% acquiring the virus by the age of 2 years.2 Of the two species, HHV-6B makes up the vast majority of symptomatic primary infections in infants

3

and is the

causative agent of exanthema subitum, also known as roseola infantum. Reactivation of HHV-6 is common after hematopoietic stem cell transplant (HCT), especially cord blood transplants (CBT). A 2012 meta-analysis reported that 34.7% of HCT recipients developed HHV-6 reactivation, which increases to 72.0% for CBT recipients.4 HHV-6 encephalitis occurs about 8 times more frequently in CBT patients compared to recipients of HCT from other sources;4 there is also reportedly an increased incidence of HHV-6 encephalitis in CD45RA-depleted transplant recipients, however further study is needed to confirm this association.5 HHV-6 encephalitis is characterized by confusion, amnesia, and general cognitive decline (i.e. altered mental status) and is diagnosed by detecting HHV-6 DNA in CSF ± brain imaging (e.g. MRI). HHV-6 encephalitis is associated with significant morbidity and mortality: approximately 20% of patients who develop HHV-6 encephalitis do not survive and nearly 40% of those who do survive suffer

significant sequelae. Studies have shown that early detection and aggressive treatment can improve clinical outcomes6. Syndrome of inappropriate antidiuretic hormone secretion (SIADH) is considered a symptom of human herpesvirus 6 (HHV-6) encephalitis.7 An increasing number of HHV-6 encephalitis cases have been associated with hyponatremia and SIADH. However, it is not yet established that SIADH is useful as an early indicator. SIADH is a common complication of hematopoietic cell transplantation (HCT), especially in young children under the age of 4 years. A single center study observed that 40% (56/140) of HCT recipients developed hyponatremia and 28.6% (16/56) of these were due to SIADH.9 The mechanism(s) by which hyponatremia and SIADH develop in HCT recipients are not fully known, although viral infections, especially HHV-6, are suspected. In 2014, Toriumi et al. set out to define the relationship between HHV-6 reactivation (defined as HHV-6 DNAemia) and SIADH in HCT recipients.10 Their results indicated a strong correlation between SIADH and HHV-6B reactivation: 78.6% of SIADH patients had HHV6B reactivation vs. 25.8% of patients without SIADH (p<0.001). Four patients from this study displayed signs of central nervous system (CNS) infection after transplantation, all of whom also had SIADH. Two of those patients were diagnosed with HHV-6 encephalitis and the other two suffered severe neurological sequelae. Based on their findings, the investigators recommended that HHV-6B reactivation in HCT patients with SIADH should prompt evaluation for CNS disease.

Central diabetes insipidus (CDI) represents the other side of serum sodium control and is characterized by a decrease in ADH synthesis and secretion. This often results in hypernatremia, a serum sodium level greater than 145 mEq/L. The common causes of CDI include genetic mutation in the hypothalamus, brain tumors, and trauma or surgery near the hypothalamus or pituitary stalk. Because the pathology of CDI originates in the same region of the brain as SIADH, we decided to include cases of hypernatremia and CDI associated with HHV-6 encephalitis in this review as well. However, reports of hypernatremia associated with HHV-6 encephalitis only accounted for 15% of the cases we found. The purpose of this study is to assess the suitability of sodium imbalance as a potential marker for HHV-6 encephalitis prior to symptom onset.

Methods A systematic review of publications indexed in the PubMed database and Google Scholar was performed for studies published since 1 January 2000 using combinations of relevant terms. Independent searches were performed for the terms ‘hyponatremia’, ‘SIADH’, ‘hypernatremia’, ‘diabetes insipidus’, paired independently with ‘HHV-6 encephalitis,’ ‘herpesvirus-6 encephalitis’, and ‘HHV6 encephalitis’ (12 total independent searches). Inclusion was based on whether the time of onset of sodium imbalance relative to the onset of HHV-6 encephalitis was described (Figure 1). This systematic review was performed according to PRISMA guidelines.11

Results Our search for HHV-6 encephalitis associated with sodium imbalance yielded 18 distinct original papers that matched our criteria. Among those were 9 case reports, 2 prospective studies, and 3 retrospective cases which described 35 cases of HHV-6 encephalitis that documented sodium imbalance and the timing of that imbalance relative to the onset of encephalitis (Figure 1). One case of hypernatremia was excluded due to lack of description regarding the time of onset, leaving 34 remaining cases.12-25 Thirty-three cases described patients who had undergone HCT with only one describing primary infection19 (Table 1). In 94% (32/34) of these cases, SIADH/ DI was the presenting symptom or occurred before the onset of HHV-6 encephalitis. In 6% (2/34), the sodium imbalance occurred after the onset of encephalitis. Cases of hyponatremia were more common, making up 85% (29/34) HHV-6 encephalitis cases associated with sodium imbalance. Most cases did not provide an exact time for the onset of sodium imbalance relative to the onset of encephalitis. Those that did reported that sodium imbalance can precede the onset of encephalitis by 1-9 days. Diagnostic imaging, primarily MRI, was performed in 19 cases, of which 17 (89%) showed clear signs of inflammation or infection to the limbic system. None of those images indicated direct hypothalamic involvement. Two cases indicated pathological processes of infection in the posterior pituitary, one via immunohistochemistry and one via MRI. No other cases indicated damage or infection in the posterior pituitary.

Discussion Given the high mortality (~20%) and morbidity secondary to HHV-6 encephalitis6, improved diagnostic techniques, prophylactic strategies, and therapeutic interventions are needed. Serum sodium levels stand out as an important potential biomarker. While SIADH is already considered a symptom of HHV-6 encephalitis, it is not widely accepted as a potential early indicator. Based on current studies, CDI does not appear to be an effective early indicator of HHV-6 encephalitis due to its low incidence, but still may be associated with HHV-6 encephalitis. In many of the cases reviewed, serum sodium was only reported at the onset of encephalitis making it difficult to determine its predictive value at this time. The presence of HHV-6 DNA in the CSF is typically used to diagnose HHV-6 encephalitis. However, the presence of HHV-6 DNA in the CSF is transitory so CSF testing could be negative due to timing. In some centers, HHV-6 encephalitis was presumed when HHV-6 DNA was present in the plasma with CNS symptoms in absence of other causes. Peak plasma HHV-6 DNAemia coincides approximately with the onset of CNS dysfunction26 so testing for HHV-6 outside of a limited time frame may result in underestimating the prevalence of HHV-6 encephalitis. One of the studies included in this review by Murakami et al., explored the clinical significance of hyponatremia in cases of HHV-6 encephalitis by retrospectively evaluating 16 patients with HHV-6 encephalitis or myelitis.14 Eleven patients had HHV-6 myelitis. Five patients had HHV-6 encephalitis, four of which were also complicated by myelitis. All five cases of encephalitis were strongly associated with hyponatremia. Being a retrospective study, no tests were done to formally diagnose SIADH. Similarly, a study by Yoshimoto et al.

reported that none of their HHV-6 myelitis-only subjects (n=11) demonstrated hyponatremia, whereas 31% (4/13) of the HHV-6 encephalitis subjects did.27 The progression and mechanism(s) of sodium imbalance in HHV-6 encephalitis patients remains unclear. Few reports observed both hypernatremia and hyponatremia in the same patient. However, the one study that did observe the development of both forms of sodium disturbance in patients reported that in most cases hypernatremia occurred first.15 If the reverse was true, i.e. low sodium levels preceded high sodium levels, one could speculate that infection and inflammation in the posterior pituitary leads to hypertrophy, causing hypersecretion of ADH and subsequent hyponatremia. As the infection progresses, atrophy and/ or damage in the posterior pituitary leads to hyposecretion of ADH and hypernatremia. However, hyposecretion followed by hypersecretion may suggest the role of other hormones or other CNS dysfunctions. The high prevalence of limbic damage found in radiographic tests may be indicative of infectious mechanisms for sodium imbalance. The limbic system encompasses several brain structures, one of which is the hypothalamus, a key structure of serum sodium control. Among the studies we reviewed, only two cases indicated direct damage and/or infection of the posterior pituitary, and none indicated direct damage and/or infection of the hypothalamus. Interestingly, both those cases that showed direct effects on the posterior pituitary were associated with CDI. Tasaka et al. observed hypernatremia in a patient after the onset of encephalitis.25 MRI showed an absence of high-intensity signals in the T1 weighted images of the posterior pituitary indicating atrophy which is consistent with CDI being the cause of hypernatremia.

However, MRI alone should not be the sole determinant for the presence of HHV-6 in specific brain structures. The second study that indicated HHV-6 infection in the posterior pituitary, by Kawamoto et al., provides an example for the possibility of HHV-6 infection without indications of pathogenesis via MRI.28 Immunohistochemistry revealed the presence of HHV-6 in the posterior pituitary of an HHV-6 encephalitis patient with CDI. The MRI did show signs of HHV-6 in the limbic system, though not specifically in the hypothalamus, nor did it show obvious signs of damage to the posterior pituitary. Furthermore, infection in the tissues surrounding the hypothalamus and posterior pituitary may also contribute to sodium imbalance through indirect pathways. There is evidence that the inflammatory cytokine, IL-6, may play a physiological role in sodium balance, specifically as a potential stimulant of ADH secretion.29,30 Several studies have documented increased levels of IL-6 in cases of HHV-6 encephalitis and other HHV-6 associated CNS dysfunctions.26,31-36 IL-6 may also play a role in neuronal tissue damage in the brain. While it does not appear to directly damage brain tissue, it can increase inflammation and level of molecules like iNOS which lead to free radical injury.37-39 High levels of IL-6 also trigger increases in cortisol which may contribute to herpetic reactivation.40-42 Given that elevated IL-6 often precedes the onset of HHV-6 encephalitis, IL-6-induced cortisol secretion may contribute to the progression of HHV-6 reactivation to HHV-6 encephalitis. SIADH has also been associated with cases of primary HHV-6 infection and reactivation without encephalitis. In a brief case study, Shimura et al. discuss two cases of SIADH in pediatric patients with exanthem subitum.43 Both patients suffered from CNS

dysfunction, but were diagnosed with encephalopathy rather than encephalitis. No HHV-6 DNA was found in the CSF and cytokine levels were not evaluated. Three previous case reports44-46 referenced by Shimura et. all observed similar cases of exanthem subitum with SIADH.43 In all three cases, the patients experienced seizures and impairment of consciousness until the hyponatremia subsided. In 2013, a 20 year old man developed SIADH following HCT.47 The patient displayed no CNS symptoms and MRI did not indicate encephalitis. However, HHV-6 reactivation was noted and suggested as a potential cause of SIADH. Cases such as these support how hyponatremia can develop before the onset of encephalitis. Further studies are needed to study the association between sodium imbalance and HHV-6 reactivation without encephalitis. In 2019, a case of a 67-year-old man who developed SIADH with DIHS associated with HHV-6 reactivation was reported.48 The investigators attributed the SIADH to the development of interstitial pneumonia, although the patient did show signs of HHV-6 reactivation. Idiopathic pneumonia has been linked to HHV-6 infection, however, in such cases, HHV-6 is typically found only in bronchoalveolar lavage fluid and not in the plasma.49,50 There have also been documented cases of SIADH being associated with druginduced hypersensitivity syndrome/drug reaction with eosinophilia and systemic symptoms (DIHS/DRESS). DIHS/DRESS is a common complication of HCT and an additional risk factor for HHV-6 reactivation.51 However, many cases of HHV-6 reactivation with DIHS/DRESS go unrecognized because testing for HHV-6 is not standard outside of Japan. The combination of SIADH with DIHS/DRESS may warrant testing for HHV-6 viremia. In

this review, we found one case of DIHS/DRESS with sodium imbalance and HHV-6 encephalitis. The patient was admitted and diagnosed with DIHS/DRESS.24 On day 11 of hospitalization, the patient suffered acute impairment of consciousness. Two days later (day 13) the patient developed hyponatremia due to SIADH despite sodium levels being previously normal. MRI confirmed limbic encephalitis. No HHV-6 DNA was found in the CSF, but there was a sharp increase in the presence of HHV-6 DNA and antibodies in the blood that coincided with acute impairment of consciousness. In rare cases, SIADH has also been associated with other forms of encephalitides or CNS dysfunction due to other herpetic infections, such as herpes zoster and human cytomegalovirus.52-55 There have also been reports of non-viral encephalitis with SIADH like autoimmune encephalitis and tick-borne encephalitis.56,57 Neither of these reports checked for infection by HHV-6. Conclusion SIADH should be considered a possible early indicator for HHV-6 encephalitis in the appropriate clinical context (e.g. recent allogeneic hematopoietic stem cell recipient). Future studies are warranted to elucidate the role of HHV-6 infection in symptomatic sodium imbalance especially in post-HCT or otherwise immunosuppressed patients.

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Figure 1: Flowchart of inclusion criteria

Table 1: Patient data Patient # Author

Age

Sex

Sodium Condition

Diagnosis

Nadir / Peak Sodium Level

Timing of Sodium Imbalance Before

1

Kawaguchi et al.

45

F

Hyponatremia

SIADH

109

2

Suzuki et al.

4

M

Hyponatremia

SIADH

120

3

Murakami et al.

47

NR

Hyponatremia

NR

4

Murakami et al.

47

NR

Hyponatremia

5

Murakami et al.

47

NR

Hyponatremia

6

Shimazu et al.

54

NR

7

Shimazu et al.

54

8

Chik et al.

Before

129.1

†

Before

NR

129.1

†

Before

NR

129.1

†

Before

Hyponatremia

NR

NR

Before

NR

Hyponatremia

NR

NR

Before

9

M

Hyponatremia

NR

113

Before

†

†

†

††

††

9

Howell et al.

14

M

Hyponatremia

NR

NR

Before

10

Howell et al.

1.5

F

Hyponatremia

NR

NR

Before

11

Howell et al.

2.8

M

Hyponatremia

NR

NR

Before

12

Chik et al.

6

F

Hyponatremia

NR

124

Before/ At Onset

13

Seeley et al.

56

M

Hyponatremia

SIADH

126

Before/ At Onset

14

Seeley et al.

53

M

Hyponatremia

SIADH

130

Before/ At Onset

15

Seeley et al.

60

M

Hyponatremia

SIADH

118

Before/ At Onset

16

Seeley et al.

36

M

Hyponatremia

SIADH

129

Before/ At Onset

17

Seeley et al.

32

M

Hyponatremia

SIADH

128

Before/ At Onset

18

Seeley et al.

41

M

Hyponatremia

SIADH

126

Before/ At Onset

19

Seeley et al.

22

M

Hyponatremia

SIADH

130

Before/ At Onset

20

Seeley et al.

38

M

Hyponatremia

SIADH

126

Before/ At Onset

21

Rantala et al.

1.2

F

Hyponatremia

NR

127

Before/ At Onset

22

Cheng et al.

9.4

M

Hyponatremia

NR

NR

At Onset*

23

Cheng et al.

8.2

F

Hyponatremia

NR

NR

At Onset*

24

Mata et al.

28

F

Hyponatremia

SIADH

NR

At Onset*

25

Oevermann et al.

11

F

Hyponatremia

SIADH

NR

At Onset*

26

Raspall-Chaure et al.

6

M

Hyponatremia

NR

122

27

Murakami et al.

47

NR

Hyponatremia

NR

28

Murakami et al.

47

NR

Hyponatremia

NR

29

Sakuma et al.

68

M

Hyponatremia

SIADH

115

After

30

Shimazu et al.

54

NR

Hypernatremia

NR

NR

Before

31

Shimazu et al.

54

NR

Hypernatremia

NR

NR

Before

32

Shimazu et al.

54

NR

Hypernatremia

NR

NR

Before

33

Shimazu et al.

54

NR

Hypernatremia

NR

NR

Before

34

Tasaka et al.

70

M

Hypernatremia

CDI

NR

After

†

†

††

††

††

††

At Onset*

129.1

†

At Onset

129.1

†

At Onset

Individual patient values not described, indicates median value of all reported cases included in this review.

†

Indicates median value of group that includes individuals from the same study, but not included in this review

††

*Patient presented with sodium condition on admission. NR = not reported.