Key words: lentiform fork, haloperidol, uremia, MRI
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”.
Case presentation :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. differential diagnosis, investigations and treatment : The
initial laboratory tests were: WBCs 11×103 cells/ml,
RBCs 3.3×106 cell/ml, Hb 10.5 mg/dl, platelets
170×103/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.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.
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 γ-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)