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\title{Lentiform Fork sign: A unique MRI image. Is there a metabolic acidosis?}



\author[1]{Ayham Alhusseini}%
\author[1]{Suaad Hamsho}%
\author[2]{Hadi Alabdullah}%
\author[3]{Mohammed  Alaswad}%
\author[4]{Mouhammed Sleiay}%
\author[5]{Omar Alsamarrai}%
\affil[1]{Damascus University Faculty of Medicine}%
\affil[2]{University of Hama College of Human Medicine}%
\affil[3]{University of Hama,Faculty of Medicine}%
\affil[4]{University of Hama}%
\affil[5]{Damascus University}%


\vspace{-1em}



  
  \date{May 22, 2024}


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\textbf{Abstract} :

\textbf{Background:} A noval radiologic sign in patients with renal
failure and UE with metabolic acidosis has recently been identified as
the lentiform fork sign. On magnetic resonance imaging (MRI), the
''lentiform fork sign'' has been described as bilateral symmetrical
hyperintensities in the basal ganglia encircled by a hyperintese rim
delineating the lentiform nucleus. Changes in uremic solute retention,
aberrant blood-brain barrier transport, disorderd vascular reactivity,
altered electrolyte and acid-base balance, and altered hormone
metabolism are the most likely causes of the condition.

\textbf{Case presentation} : 56-year-old man with end-stage renal
disease was brought to the emergency room for a progressive change in
mental status and involuntary arm movements over the previous five days,
which were also accompanied by mild dyspnea.

A brain MRI was performed, and it revealed hyperintensity on T2/FLAIR in
the white matter surrounding the basal ganglia. The haloperidol was
stopped, and there more dialysis sessions were carried out.

\textbf{Conclusion} : intensified hemodialysis and glycemic control are
the cornerstones of treating DUS with likely reversible clinical
symptoms and remission of imaging abnormalities.

\textbf{Key words: lentiform fork, haloperidol, uremia, MRI}

\emph{Introduction:}Uremic Encephalopathy is common in patients with
either acute or chronic renal failure, patients with severe renal
failure may develop toxic-metabolic encephalopathy as a consequence of
endogenous uremic toxins. (1) The disorder is most likely caused by
changes in uremic solute retention, abnormal blood-brain barrier
transport, disturbed vascular reactivity, altered electrolyte and
acid-base balance, and changed hormonal metabolism. The pathogenesis is
uncertain and complicated. (2) The diagnosis is frequently confirmed
after the improvement of the patient's symptoms following dialysis or
transplantation.(2)

The ''Lentiform fork sign'' has been reported on magnetic resonance
imaging (MRI), and is shown as bilateral symmetrical hyperintesities in
the basal ganglia surrounded by a hyperintense rim delineating the
lentiform nucleus. It has been postulated to result from cases of severe
metabolic acidosis, such as metformin-associated encephalopathy,pyruvate
dehydrogenase deficiencies, uremic encephalopathy, propionic acidemia,
mithochondrial diseases, and methanol/ethylene glycol intoxication.(3)
Here we report a case of a 56-year-old patient with uremic
encephalopathy in the setting of renal failure, presented with a unique
MRI finding ''Lentiform fork sign''.

\emph{Case presentation :}\textbf{case history:} A 56-year-old man with
end-stage renal disease is brought to the emergency department for a
progressive altered mental status and involuntary arm movements
associated with mild dyspnea over the last 5 days. The patient was
diagnosed four months ago with end-stage renal disease due to
long-standing uncontrolled type 2 diabetes mellitus and hypertension and
he was programmed on hemodialysis three times a week. In the emergency
department, his vital signs were as follows: temperature 37.2, blood
pressure 140/90 mmHg, heart rate 95 bpm, O2 saturation 95, the patient
was tachypneic (RR= 28) with mild distress. The patient was lethargic,
disoriented, and aroused with vocal stimuli on physical examination.
Pupils were sluggishly reactive to light. Tremor and asterixis were
noted without nuchal rigidity or any other focal neurological signs. He
had bilateral diminished breath sounds at lung bases and pitting edema
in the lower extremities.~\textbf{differential diagnosis, investigations
and treatment} : The initial laboratory tests were: WBCs
11\selectlanguage{ngerman}×10\textsuperscript{3} cells/ml, RBCs 3.3×106 cell/ml, Hb 10.5 mg/dl,
platelets 170×10\textsuperscript{3}/ml, Urea 205 mg/dl, Creatinine 1.2
mg/dl, Glucose 99 mg/dl, Sodium 139 mg/dl, Potassium 5.9 mg/dl, the
Arterial blood gases (ABGs): PH=6.9, HCO3 = 2.2 mEq/L, PO2 = 100 mmHg,
PCO2~ = 11.4 mmHg, which is consistent with severe metabolic acidosis.
Sodium bicarbonate was infused to correct the acidosis, and an emergent
hemodialysis session was conducted. After that, the patient was admitted
to the ICU, until he was stabilized. The ABGs were re-evaluated after 12
hours and showed: PH=7.19, HCO3 = 11 mEq/L, PCO2= 22 mmHg, PO2=98 mmHg.
The patient then regained his consciousness and was alert and oriented.
However, the tremor and asterixis remained.

A brain MS CT showed areas of hypodensity at the level of the basal
nuclei on both sides of the midline, which may be in the context of
hypoxia or metabolic damage, senile changes, calcifications on the
midline in the frontal area (figure. 1). A brain MRI was performed and
it showed a hyperintensity on T2/FLAIR in the white matter surrounding
the basal ganglia (the internal and external capsule)(figure. 2 A, B).
These features are characteristic of lentiform fork sign (LFS) which is
pathognomic for uremic encephalopathy. Further questioning revealed that
the patient had missed his last couple of dialysis sessions, and he was
put on Haloperidol by his primary care physician to treat his
confusion.\textbf{outcome and follow up:} The haloperidol was stopped
and 3 more dialysis sessions were performed, and after 10 days all of
his symptoms and laboratory results improved immensely.

\emph{Discussion:}We describe a case of a patient with diabetes, chronic
kidney disease, severe metabolic acidosis, and uremic encephalopathy who
demonstrated a rare imaging finding called the lentiform fork sign. Wang
et al. were the first to propose a condition called `Diabetic uremic
syndrome' in diabetic patients who have end stage renal disease,
complaining of neurological symptoms, and bilateral basal ganglia
lesions. (4)(5) Manickavasagar et al. (6) suggested the term
``extrapyramidal syndromes of chronic kidney disease and dialysis''
(EPS-CKDD)'' in a retrospective case series review of 20 patients
receiving dialysis. The diagnostic criteria were based on the
presentation of an acute extrapyramidal movement disorder manifesting
either as hypokinetic acute parkinsonism or a hyperkinetic form with
acute chorea/athetosis associated with bilateral basal ganglia injury.
The key risk factors for EPS-CKDD were type 2 diabetes, metformin use,
dialysis, female sex, and potentially thiamine deficiency. Metabolic
acidosis, elevated lactate, and thiamine deficiency were the related
laboratory abnormalities. The study also indicated that early
recognition and treatment of the condition may improve outcomes. (6) Our
case presentation supports the suggested diagnostic criteria of EPS-CKDD
as the patient was on hemodialysis for end-stage renal disease,
diabetic, complained of extrapyramidal symptoms, demonstrated lentiform
fork sign on imaging, and his laboratory analysis disclosed severe
metabolic acidosis (PH= 6.9). Uremic encephalopathy (UE) is a neurologic
complication associated with acute or chronic renal failure that causes
acute or subacute onset of reversible neurologic symptoms. (7) The
symptoms of UE are most likely caused by the harmful effects of
neurotoxic compounds. The accumulation of uremic toxins, such as
guanidine compounds, can increase the neurotoxic effects of excitatory
N-methyl-D-aspartate receptors. Additionally, the inhibition of
inhibitory \selectlanguage{greek}γ-\selectlanguage{english}aminobutyric acid receptors may also contribute
significantly to the development of UE. (8) Signs of UE may include
altered mental status, movement disorder (asterixis, myoclonus, tremor),
and cognitive impairment. (9) The basal ganglia are susceptible to
damage from various toxins and metabolic disturbances. (10) Lentiform
fork sign was recently described as a unique radiologic sign in patients
with renal failure and UE with metabolic acidosis. A similar lesion has
also been described in patients with normal renal function who had
metabolic acidosis secondary to various other causes, suggesting that
metabolic acidosis is an essential element in pathogenesis. (11)
Vasogenic edema of the lentiform nuclei is the underlying cause of this
condition. It has been documented in cases of uremic encephalopathy, as
well as in patients affected by methanol and ethylene glycol toxicity,
propionic acidemia, pyruvate dehydrogenase deficiency, and mitochondrial
disorders. (12) It also can be observed in metformin-associated
encephalopathy (ME). (13). However, despite the strong association that
has been reported in many cases between diabetic uremic syndrome with
lentiform fork sign and metformin use, our patient was not using
metformin in his medication regimen. The elements of the lentiform fork
sign are: 1) the lateral arm, formed by the edematous external capsule
and extending from the anterior end of the putamen to the stem; 2) the
stem, created by merging of the edematous external and internal capsules
at the inferoposterior end of the putamen; and 3) the medial arm, which
extends from the stem anteriorly up to one-third of the medial edge,
where it splits into two slightly less T2/FLAIR-hyperintense branches
engulfing the globus pallidus.(12) In this case, considering the rapid
onset of movement and consciousness disturbance immediately before
admission, the diabetic uremic syndrome with lentiform fork sign may
have occurred with haloperidol--induced extrapyramidal symptoms which
exacerbated the movement manifestations. Also, another contributing
factor is haloperidol induced lactate elevation (14), which may have
played a role in inducing this rare MRI finding. It has been hinted in
some studies that lactate elevation in haloperidol and other
antipsychotics may be an important biomarker in extrapyramidal symptoms
development(15) Correction of metabolic acidosis with intensive
hemodialysis and glycemic control is the cornerstone of treatment of DUS
with potential reversible clinical manifestations and resolution of
imaging findings. Withdrawal of metformin and thiamine supplementation
may also be considered in the management. (13) (6) It is important to be
aware of the potential increase in blood lactate levels and
extrapyramidal side effects when using haloperidol. Therefore,
prescribing antipsychotics with a lower risk of adverse effects is
recommended. (14) (15)

\textbf{Conclusion :}

The lentiform fork sign is a pathognomonic MRI finding for uremic
encephalopthay, especially when it's associated with extrapyramidal
movements. It is of great importance to recognize and treat movement
disorders in patients with ESRD and dialysis, and physicians should keep
in mind the effect of metabolic disturbances on the neurotransmitters of
the brain, and must always consider the adverse reaction of the
prescribed drugs (such as haloperidol) and their impact on their
patients.

\emph{References} :

1. Seifter JL, Samuels MA. Uremic encephalopathy and other brain
disorders associated with renal failure. InSeminars in neurology 2011
Apr (Vol. 31, No. 02, pp. 139-143). \selectlanguage{ngerman}© Thieme Medical Publishers

2. Rosner MH, Husain-Syed F, Reis T, Ronco C, Vanholder R. Uremic
encephalopathy. Kidney International. 2022 Feb 1;101(2):227-41.

3. Finelli PF, Singh JU. A syndrome of bilateral symmetrical basal
ganglia lesions in diabetic dialysis patients. American journal of
kidney diseases. 2014 Feb 1;63(2):286-8 4. Wang HC, Cheng SJ. The
syndrome of acute bilateral basal ganglia lesions in diabetic uremic
patients. J Neurol. 2003 Aug;250(8):948--55. 5. Sakurai T, Nishida H.
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GANGLIA NEUROTOXINS. Neurol Clin. 2000 Aug;18(3):665--80. 11. Rathi M,
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14. Glavina T, Mrass D, Dodig T, Glavina G, Prani\selectlanguage{polish}ć \selectlanguage{english}S, Ugle\selectlanguage{polish}š\selectlanguage{english}i\selectlanguage{polish}ć \selectlanguage{english}B. Blood
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