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\begin{document}

\title{Topical Betadine Exposure Precipitating Sterile Cerebritis and Systemic
Iodine Toxicity}



\author[1]{Cody Rasner}%
\author[1]{Timothy Allen}%
\author[1]{Meredith Kavalier}%
\affil[1]{University of Minnesota Medical School Twin Cities Campus}%


\vspace{-1em}



  
  \date{May 27, 2024}


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Topical Betadine Exposure Precipitating Sterile Cerebritis and Systemic
Iodine Toxicity

\textbf{Authors}

Cody Rasner, MS \textsuperscript{1}, Timothy Allen,
MD\textsuperscript{1}, Meredith Kavalier, MD\textsuperscript{1}

1 University of Minnesota Medical School

\textbf{Key Clinical Message}

Cerebritis may present with encephalopathy, seizures, localizing
neurologic deficits, or death. Betadine is an antimicrobial solution
with high iodine content, and iodine has well-known toxicity. Here we
report a case of sterile cerebritis secondary to repeated betadine
exposure from caring for an extensive open wound of the scalp.

\textbf{Background}

Cerebritis is a potentially fatal inflammatory condition typically with
presenting symptoms of encephalopathy, seizures, or localizing
neurologic deficits. Common culprits of cerebritis include autoimmune
conditions as well as infectious causes.

Betadine (or povidone-iodine) is a commonly used antiseptic, made up of
a combination of iodine and a water-soluble
polymer.\textsuperscript{1}Once applied, the iodine molecule dissociates
and penetrates microbial cell membranes, interacts with proteins,
nucleotides, and fatty acids within the cell, and ultimately results in
rapid cell death.\textsuperscript{1} This mechanism of action promotes a
wide antimicrobial spectrum as well as efficacy in disrupting
biofilms.\textsuperscript{1,2}

Betadine may cause irritant dermatitis when applied to the skin. This
develops as iodine exerts similar destructive effects to those mentioned
previously. The effect of betadine on neural tissue is less understood.
In a study evaluating varying concentrations of betadine on rabbit
brains, Li et. al. describe histologic evidence of neural tissue damage
in the absence of clinical indications of such damage, and tissue damage
worsened with increasing concentrations.\textsuperscript{3} This
evidence is further supported by Wang et. al. who noted that lower
concentrations of betadine (eg. 0.5\%) was beneficial for tissue healing
but higher concentrations (eg. 5\% or more) had the opposite
effect.\textsuperscript{4} To our knowledge there are no reports of
iodine toxicity resulting in sterile cerebritis secondary to recurrent
topical betadine application. Here we report an interesting presentation
of sterile cerebritis precipitated by chronic topical betadine
application during the care of an open scalp wound.

\textbf{Objective}

Here we report an interesting presentation of sterile cerebritis
precipitated by chronic topical betadine application during the care of
an open scalp wound.

\textbf{Case Report}

A 73-year-old woman with a pertinent past medical history of diabetes
and squamous cell carcinoma (SCC) of the scalp presented with her family
to her primary care provider for her annual Medicare visit (2/2023).
During the visit, her family reported increased confusion and falls over
the course of two weeks as well as increased foul smelling, purulent
drainage emanating from a surgical site wound on her scalp. Review of
systems was negative for fever, chills, headaches, dizziness,
hypoglycemia, or other infectious symptoms. She reported taking her
medications as prescribed. In addition, her PHQ score was 18 (previous
was one in December 2021).

Physical exam revealed normal vital signs and an intact cranial surgical
mesh with an adjacent area of hypertrophied, hardened skin and purulent
drainage. Bloodwork from the visit revealed a mild leukocytosis of
11.9k/cu mm (4.5 -- 11k/cu mm), elevated ESR and CRP of 75 and 11.7
(\textless{}30 and \textless{}0.5 respectively), and an elevated
hemoglobin A1c of 10.3\% (6.2\% six months prior). With these results, a
prompt evaluation in the nearest emergency department (ED) was
recommended to assess for a central nervous system (CNS) infection.

The SCC of her scalp had previously eroded through her cranium to the
dura, resulting in craniectomy with placement of a titanium fenestrated
mesh. To close the defect, she underwent two flap procedures (most
recently 4/2022); however, both attempts were unsuccessful. Not wanting
to undergo additional procedures, the defect had been treated for at
least six months using Betadine 10\% solution which was discontinued two
weeks prior to her presentation to her primary care clinic.

In the ED, her vitals were: 97.9F, heart rate 69, respiratory rate 20,
blood pressure 110/45, and O2 saturation 100\% on room air. She was
alert and oriented with an intact surgical mesh on her head. The
surgical site had clean, dry dressing wrapped around it. The surgical
site was surrounded by brown/gray material that appeared to be a mix of
matted hair and dried discharge without any obvious purulence, foul
smell, or tenderness (Figure 1 A \& B).

After obtaining initial bloodwork (Table 1) and blood cultures, she
underwent imaging, a lumbar puncture (Table 2), wound cleaning (Figure 1
C \& D), and was started on intravenous antibiotics and supportive cares
(vancomycin, cefepime, and metronidazole at CNS penetration dosing).

Magnetic resonance imaging (MRI) of her brain revealed left frontal
cerebritis with associated bifrontal leptomeningitis and pachymeningitis
without any intra- or extra-axial abscess. After discussing the case
with Neuroradiology and comparing current imaging (Figure 2) to images
obtained one year prior (Figure 2), there were no significant changes
noted in the primary area of concern.

\textbf{Discussion}

Betadine is a topical antimicrobial agent with a large iodine content
frequently used for wound care. Excessive iodine intake has
well-characterized toxicities within the body. Specifically, elevated
serum levels of iodine may lead to thyroid dysfunction resulting in both
psychological and metabolic effects. In this patient, iodine likely
permeated tissues during wound care therein entering the meninges.
Furthermore, iodine absorption is enhanced on denuded skin or other
tissues without a protective barrier. \textsuperscript{5} Every
milliliter of betadine 10\% contains 10 mg of iodine. Once iodine is
absorbed, it reaches equilibrium rapidly with the extracellular space
and distributes evenly except in certain areas, one of which is the
thyroid where it is used to make thyroxine (T4) and triiodothyronine
(T3). Excessive iodine may result in a transient reduction in thyroid
hormone synthesis (Wolff-Chaikoff effect) by inhibiting thyroid
peroxidase (TPO) activity.\textsuperscript{6} Iodine also prevents the
release of preformed thyroid hormones (called the Plummer effect) by
inhibiting proteolysis of thyroglobulin.\textsuperscript{6} Upon
checking her thyroid status, she was found to have a low normal TSH at
0.44 (0.3 -- 4.2) and a low normal FT4 at 1.1 (0.9 -- 1.7).

A reduction in thyroid hormone influences other organs, such as the
pancreas and the brain. In the pancreas, it may lead to decreased
insulin secretion, via decreased stimulatory signal on pancreatic beta
cells, thus leading to hyperglycemia and worsening of
diabetes.\textsuperscript{7} In the brain, reduced thyroid hormones may
result in pseudo-depression due to alterations in metabolic activity of
neurons. \textsuperscript{8} Thinking back at our patient's initial
presentation to her PCP, we suspect that the systemic absorption of
iodine from betadine was exacerbating her chronic medical conditions
leading to her worsening mood and diabetes despite taking her
medications as prescribed. Given that the half-life of iodine is about
66 days, we theorize that her actual plasma iodine level was much
higher.

Given the lack of significant differences seen on imaging as well as her
benign physical exam and lab results, we suspected that the patient had
a chronic sterile cerebritis due to the Betadine used in wound cares and
an acute soft tissue infection of the scalp. We theorized that the
irritation seen on imaging resulted from Betadine exposure via seepage
thru the cranial mesh fenestration. To confirm this theory, a serum
iodine level was obtained which returned elevated at 404 (normal: 40 --
92). Unfortunately, we were unable to obtain an iodine level from the
CSF as no such test exists.

During her hospital course, her creatinine improved with intravenous
fluids and was determined to be secondary to dehydration from poorly
controlled diabetes. She declined any additional procedures to close the
defect. Despite being on broad spectrum antibiotics, she began to
experience new episodes of confusion. Repeat imaging revealed new
enhancement of the scalp overlying the craniectomy defect as well as
extra-axial abscess formation, concerning for a worsening scalp
infection with involvement of the mesh. The patient was ultimately
discharged home on hospice with empiric oral antibiotics for the scalp
soft tissue infection and new wound care instructions (using Vashe
moistened sterile gauze rather than betadine to avoid worsening of
condition).

\textbf{References}

\begin{enumerate}
\tightlist
\item
  P.L. Bigliardi \emph{et al.}Povidone iodine in wound healing: a review
  of current concepts and practices Int. J. Surg. (2017)
\item
  \emph{Prescribers' Digital Reference} . Betadine 5\% (povidone iodine)
  dose, indications, adverse effects, interactions\ldots{} from PDR.net.
  (n.d.). Retrieved February 24, 2023, from
  https://www.pdr.net/drug-summary/Betadine-5--povidone-iodine-2152.1400
\item
  Li SH, Wang Y, Gao HB, Zhao K, Hou YC, Sun W. Experimental study on
  the toxicity of povidone-iodine solution in brain tissues of rabbits.
  Int J Clin Exp Med. 2015 Sep 15;8(9):14863-70. PMID: 26628968; PMCID:
  PMC4658857.
\item
  Wang, D., Huang, X., Lv, W. and Zhou, J. (2022), The Toxicity and
  Antibacterial Effects of Povidone-Iodine Irrigation in Fracture
  Surgery. Orthop Surg, 14:
  2286-2297.\emph{https://doi.org/10.1111/os.13422}
\item
  Dela Cruz F, Brown DH, Leikin JB, Franklin C, Hryhorczuk DO. Iodine
  absorption after topical administration. West J Med. 1987
  Jan;146(1):43-5. PMID: 3825108; PMCID: PMC1307179.
\item
  Farebrother, J., Zimmermann, M.B. and Andersson, M. (2019), Excess
  iodine intake: sources, assessment, and effects on thyroid function.
  Ann. N.Y. Acad. Sci., 1446:
  44-65.\emph{https://doi.org/10.1111/nyas.14041}
\item
  Biondi B, Kahaly GJ, Robertson RP. Thyroid Dysfunction and Diabetes
  Mellitus: Two Closely Associated Disorders. Endocr Rev. 2019 Jun
  1;40(3):789-824. doi: 10.1210/er.2018-00163. PMID: 30649221; PMCID:
  PMC6507635.
\item
  Mirella P. Hage, Sami T. Azar, ``The Link between Thyroid Function and
  Depression'', Journal of Thyroid Research, vol. 2012, Article ID
  590648, 8 pages, 2012. https://doi.org/10.1155/2012/590648
\end{enumerate}

\textbf{Figure Legends} :

\textbf{Figure 1} :

Initial images of patients scalp wounds upon arrival (A and B) and after
initial wound cares (C and D).

\textbf{Figure 2} :

Neuroradiologic magnetic resonance imaging during acute cerebritis
(Left) and similar imaging obtained one year prior (Right).

\textbf{Hosted file}

\verb`Figure 1.docx`  available at \url{https://authorea.com/users/611903/articles/647333-topical-betadine-exposure-precipitating-sterile-cerebritis-and-systemic-iodine-toxicity}

\textbf{Hosted file}

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\textbf{Hosted file}

\verb`Table 1.docx`  available at \url{https://authorea.com/users/611903/articles/647333-topical-betadine-exposure-precipitating-sterile-cerebritis-and-systemic-iodine-toxicity}

\textbf{Hosted file}

\verb`Table 2 .docx`  available at \url{https://authorea.com/users/611903/articles/647333-topical-betadine-exposure-precipitating-sterile-cerebritis-and-systemic-iodine-toxicity}

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