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3rd Congress of the European Academy of Neurology
Amsterdam, The Netherlands, June 24 – 27, 2017
Teaching Course 17
Neurological presentations of systemic disorders - Level 1
Encephalopathies in metabolic disorders
Karin Weissenborn Hannover, Germany
Email: [email protected]
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Conflict of interest: The author has no conflict of interest in relation to
this manuscript
Metabolic encephalopathies frequently cause the consultation of a
neurologist, both in the emergency room as well as for in-patients of
the departments of internal medicine or surgery. More than 2/3 of the
patients who are referred to an emergency unit with altered conscious-
ness show electrolyte disturbances, endocrinologic disorders, metabolic
encephalopathies or intoxications (Plum & Posner 1982). The sympto-
matology of metabolic encephalopathies is manifold – including slight
cognitive deficits and personality changes, sleep and mood alterations
as possible first symptoms of the disorder as well as increasing alteration
of consciousness from somnolence to coma, disorientation, confusion,
hallucinations, and seizures. Motor symptoms include dysarthria, ataxia,
tremor, asterixis, myocloni, choreoathetosis, dystonia, and Parkinsonism.
Of interest, even focal neurological symptoms may be observed such
as dysphasia, hemiparesis or hemichorea. Obviously the symptoms are
unspecific. However, there are some characteristic findings indicating
for example hepatic or uremic encephalopathy. Multifocal myoclonus is
characteristic for uremic encephalopathy, while extrapyramidal or
cerebellar symptoms are frequently seen in patients with liver cirrhosis
and hepatic encephalopathy (Brouns & De Deyn 2004; Seifter & Samuels
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2011, Jones & Weissenborn 1997). The diagnosis “metabolic encephalo-
pathy” can be made only after exclusion of other possible causes of brain
dysfunction. Thus, every patient with suspected metabolic encephalo-
pathy needs a thorough diagnostic work up including of course a detailed
clinical examination, consideration of the patients history and current
medication, biochemical analysis of the blood (sometimes also of the
urine or cerebrospinal fluid), brain imaging and electroencephalography
(EEG). Again, there are no specific findings for one or the other type
of metabolic encephalopathy, except of the indications of metabolic
alterations such as increased serum urea and creatinine levels suggesting
uremic encephalopathy or increased serum ammonia levels suggesting
hepatic encephalopathy. However, these findings just indicate impairment
of kidney or liver function, respectively, but do not prove uremic or
hepatic encephalopathy. Considering laboratory findings only significant
hypo- or hyperglycemia may be considered diagnostic in an individual
case. But even in patients with severe alterations of blood glucose levels
these can be taken as evidence for a metabolic alteration of brain
function only, if the patient improves within a short period after
normalization of the blood glucose levels.
Brain imaging using either cranial computer tomography (CCT) or magnetic
resonance imaging (MRI) is done for the exclusion of other than metabolic
causes of brain dysfunction, exclusively. None of the metabolic encephalo-
pathies presents with specific CCT or MRI alterations. But, again there are
some findings that hint at a metabolic cause of a patient’s neurological
symptoms. About 90 % of the patients with liver cirrhosis, for example,
show characteristic bilateral symmetric pallidal hyperintensities on T1-
weighted MR images due to manganese deposition in the brain, with
predominance in the basal ganglia (Morgan 1998; Rose et al. 1999). If a
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patient presents with psychomotor slowing and Parkinsonism this MRI
finding suggests liver cirrhosis as cause of the symptoms and gives reason
to initiate a medical diagnostic work up of the patient. Recently the
so called lentiform fork sign – a symmetric hyperintensity involving the
caudate, putamen and thalamus girdled by a bright fork-like hyperintense
rim in fluid-attenuated inversion-recovery (FLAIR) images has been
repeatedly described as a characteristic MRI finding in patients with
uremic encephalopathy (Fabiani et al. 2013; Kim et al. 2016). However,
this MRI finding does not prove uremic encephalopathy but has been
described also in patients with methanol intoxication, for example, as
well as in other conditions with metabolic acidosis (Kumar & Goyal 2010).
If a patient’s MRI shows hyperintensities in diffusion weighted images in a
region that does not correspond to the patients’ clinical symptoms
hypoglycemia should be considered and blood glucose levels checked,
immediately (Katoh et al. 2016).
The EEG shows a generalized slowing in patients with metabolic
encephalopathy with excess theta and delta activity. In uremic patients
also bilateral spike wave compexes may occur (Brouns & De Deyn 2004).
The extent of EEG alterations correlates with the extent of clinical
symptoms. However, it has been shown in patients with chronic hepatic
encephalopathy that the EEG may normalize in case of stable clinical
symptoms (Penin 1967). In general, however, the EEG alterations precede
changes in the clinical status, and thus may announce a bout of hepatic
encephalopathy in patients with liver cirrhosis or uremic encephalopathy
in patients with renal dysfunction. With successful treatment the EEG
normalizes. The improvement, however, may be delayed in uremic
patients with initiation of hemodialysis.
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Hepatic encephalopathy (HE)
Hepatic encephalopathy is a frequent complication of liver cirrhosis
and an inherent attribute of acute liver failure. Three types of HE are
differentiated: Type A in patients with acute liver failure, type B in
patients with porto-systemic shunts in the absence of liver dysfunction,
and type C in patients with liver cirrhosis. Hepatic encephalopathy is
characterized by alterations of cognition, motor function and conscious-
ness. With regard to the alteration of consciousness patients are classified
into 4 grades: HE I in case of attention deficits and psychomotor slowing,
HE II in case of lethargy and disorientation, HE III in the presence of
somnolence or semi-stupor and HE grade IV in case of coma (so called
West Haven criteria). Alterations of cognition and consciousness can be
accompanied with extrapyramidal, cerebellar and pyramidal signs in
all grades of HE. Most characteristic are hypomimia, hypokinesia, rigor,
tremor, dysarthria, dysdiadochokinesia and ataxia. Hyperreflexia and
positive pyramidal signs can be observed predominantly in patients with
grade III and IV HE, but can be present also in the other stages, on
principle. Asterixis may be present in the absence of any other alteration,
but is most frequently observed in patients with grade II or III HE.
Considering the time course of symptom development episodic, recurrent
and chronic progressive/persistent forms are distinguished. An excellent
and extensive description of the clinical presentation of HE is given by
Sherlock et al. (1954) and Summerskill et al. (1956).
The chronic progressive or persistent form of hepatic encephalopathy has
predominantly been observed in patients with extensive porto-systemic
shunts. The prevalence is unclear. We detected chronic progressive
cirrhosis-related Parkinsonism – one of the clinical features of chronic
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progressive HE – in a prospective study of 214 patients with liver cirrhosis
on the waiting list for transplantation in about 4 %. Two percent of the
patients presented with hepatic myelopathy - another rare complication
of extensive porto-systemic shunts that develops predominantly in men
with liver cirrhosis and leads to severe spastic paraparesis without any
sensory deficits or bladder or bowel disturbance within months.
Up to 60% of the patients with liver cirrhosis but no clinical symptoms of
HE show significant alterations of brain function in psychometric testing or
neurophysiological examinations such as electroencephalography (EEG).
These patients are considered to suffer from the so called minimal hepatic
encephalopathy (mHE). They show deficits in attention, visual perception,
visuo-constructive abilities, and motor speed and accuracy. Since the
patients’ language is preserved mHE remains undetected in the standard
medical examination. The characteristic pattern of cognitive deficits,
however, explains why mHE affects the working ability of blue collar
workers, predominantly, while white collar workers appear unaffected for
a long time (Schomerus & Hamster 2001). Although mHE appears to be
only of minor significance on the first view diagnosis and treatment of
mHE is recommended by experts in the field. MHE impairs health related
quality of life and working ability and it interferes with the patients
driving ability. In addition it indicates an increased risk for the develop-
ment of clinically overt HE. (Weissenborn 2015)
A diagnosis of HE can be made only after exclusion of other possible
causes of brain dysfunction. The diagnosis can be considered proven only
if the symptoms resolve with HE therapy. One of the main differential
diagnoses of HE is Wernicke’s encephalopathy. Since the rapid substitution
of thiamine is crucial in Wernicke’s encephalopathy, patients should
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be treated with 100 mg thiamine i.v. in every suspected case, before
a diagnosis can be made based on thiamine serum levels or the
characteristic MRI findings.
Several tools have been used for the diagnosis of minimal HE. Currently
the most frequently used and recommended tools are the PSE-Syndrom-
Test (available at Hannover Medical School), the assessment of the critical
flicker frequency (CFF) and EEG (Vilstrup et al. 2014).
Therapy of HE aims at the reduction of gut ammonia production and
absorption. Hyperammonemia and increased levels of inflammatory
cytokines are considered the main causes of HE. In case of increased
plasma ammonia levels increased amounts of ammonia reach the brain,
where ammonia is detoxified via glutamine production within astrocytes.
At first astrocytic osmolytes – such as myoinositol – leave the cells to
counterbalance the increasing intracellular amount of glutamine. If this
resort is spent astrocytic swelling is inevitable leading to astrocytic
dysfunction, disturbances of neuron astrocyte interaction and brain
dysfunction. Astrocyte swelling can be induced not only by increased
ammonia and inflammatory cytokine levels, but also by hyponatremia and
benzodiazepines. This observation explains why HE episodes are often
precipitated by electrolyte dysbalance, use of benzodiazepines or
infection. In these cases correction of the precipitating factor is the first
line therapy. In addition plasma ammonia level lowering drugs can be
applied. The most frequently used drug is lactulose in a daily dose of 30 -
60 mg (45-90 ml). In more severe cases lactulose may be combined with
antibiotics, such as rifaximin or metronidazole. A combination therapy
using lactulose and rifaximin for six months after a HE episode has been
shown to reduce the risk for recurrent HE and re-hospitalisation (Vilstrup
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et al. 2014; Bass et al. 2010). A further drug that can be used for the
treatment of HE is L-ornithine-L-aspartate (LOLA). So far, positive data in
regard to LOLA therapy relate to intravenous application in patients with
grades II-IV HE, predominantly (Kircheis et al. 1997).
Of note plasma ammonia level lowering therapy is of no use in patients
with cirrhosis-related Parkinsonism or hepatic myelopathy (chronic pro-
gressive HE or acquired hepatolenticular degeneration). These patients,
however, might benefit from liver transplantation early in the develop-
ment of their neurological symptoms.
In contrast to liver cirrhosis pronounced HE in acute liver failure is
frequently accompanied by significant brain edema (25 – 35 % in grade III
HE; 65 – 75 % in grade IV HE). Since intubation and mechanical ventilation
has to be performed in these patients brain edema cannot be detected by
clinical examination. Assessment of intracranial pressure by intracranial
bolds is used by some centers, but is difficult since the coagulopathy in
acute liver failure holds a significant risk of intracranial bleeding
(Karvellas et al. 2014). Cardoso and colleagues (2017) recently re-
commended the following approach to intracranial hypertension and
brain edema in patients with ALF: 1) head of the bed greater than 30°; (2)
minimize patient stimulation; (3) sedation and invasive mechanical
ventilation; (4) treat fever ; (5) treat seizures (prophylaxis has unclear
value); (6) aim for a mean arterial pressure of at least 75 mm Hg with
fluids and/or vasopressors, with the goal being to maintain an intracranial
pressure less than 25 mm Hg and a cerebral perfusion pressure greater
than 50 mm Hg; (7) consider using renal replacement therapy to promote
more effective ammonia clearance; (8) aim for a serum sodium of 145 to
155 mmol/L with hypertonic saline (3%-30% infusion) for prophylaxis in
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patients with grade III-IV HE; (9) consider using mannitol (0.5-1 g/kg
bolus) to transiently reduce intracranial pressure when there is
established intracranial hypertension (repeat if serum osmolality < 320
mOsm/L); and (10) consider using hyperventilation (aiming for a PCO2
25-30 mm Hg) in cases of established intracranial hypertension despite
optimized treatment to try to delay the progression to tonsillar
herniation.
Drugs which are used for the reduction of plasma ammonia levels in
patients with cirrhosis such as lactulose or LOLA have not shown a
significant effect in ALF; neither with regard to plasma ammonia levels,
nor with regard to survival (Lee et al. 2011, Acharya et al. 2009)
Liver transplantation is the only definitive treatment in patients with
acute liver failure. Since part of the patients has a good prognosis even
without transplantation one of the most difficult tasks in the care of ALF
patients is the risk stratification in regard to death without trans-
plantation. Several criteria have been elaborated worldwide. Currently
the most often used are the King's College criteria (O’Grady et al. 1989).
Uremic encephalopathy
Uremic encephalopathy is considered to be caused in particular by
guanidino compounds that accumulate due to renal dysfunction. These
compounds are supposed to interfere with glutamatergic as well as GABA-
ergic neurotransmission, finally leading to an enhanced excitability. In
addition secondary hyperpara-thyreoidism is suggested as leading to in-
creased neuronal calcium levels and neuroexcitation, as well (Weissenborn
& Lockwood 2015; Seifter & Samuels 2011).
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Knowledge about the pathophysiology of uremic encephalopathy,
however, is sparse compared to hepatic encephalopathy, for example,
probably due to the fact that it is to be observed today only in patients
in whom a decision has been made not to start dialysis.
Clinical symptoms range from emotional alterations, especially de-
pression, and slight attention and memory deficits to severe alterations of
consciousness and cognition including (mostly agitated) confusion,
psychosis, seizures and coma. Action tremor, asterixis and myoclonus, as
well as hyperreflexia are characteristic features of uremic encephalo-
pathy. Occasionally, choreatic movements have been described. Both
asterixis and myoclonus may be provoked by several drugs such as opioids,
antiepileptic drugs, phenothiazines or metoclopramide in patients with
impaired renal function due to increased plasma levels. This is important
in clinical practice since very often older people are referred to the
emergency unit due to an impairment of consciousness who present the
combination of diabetic renal dysfunction, pregabalin prescription for
neuropathic pain, opioid treatment for lumbar pain and chronic
metoclopramide treatment due to chronic nausea. Of note, a metabolic-
toxic encephalopathy can be suspected in these patients even in the
presence of only moderately increased creatinine and urea levels. The
diagnosis is proven if the symptoms recede after withdrawal of the drugs.
Moreover, uremic encephalopathy is proven if symptoms disappear with
successful renal replacement therapy. Usually the improvement takes
days or even weeks, and slight cognitive dysfunction may persist.
Cognitive dysfunction in patients with end-stage renal disease has other
causes in addition to the accumulation of uremic toxins, such as renal
anemia, hyperparathyreoidism and chronic obstructive sleep disorder.
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Addressing these accompanying disorders is mandatory to improve the
patients’ brain function and quality of life. Of note, hemodialysis patients
may develop thiamine deficiency. Thiamine is a water soluble vitamin,
and thus may be lost in the dialysis procedure. If this is accompanied by a
decreased ingestion of thiamine due to whatever cause the patients may
develop Wernicke’s encephalopathy (Hung et al. 2001; Ihara et al. 1999).
Hypoglycemia
Hypoglycemia is one of the main differential diagnoses in patients with
focal neurological symptoms of acute or sub-acute onset. Amazingly
severe hypoglycemia may result in speech arrest, hemiparesis, or
hemichorea, for example, but of course focal and generalized seizures and
severe disturbance of consciousness including coma may be expected
as well. Most often hypoglycemia occurs as an unintended adverse effect
of antidiabetic therapy with insulin or sulfonylureas. In treating patients
with sulfonylurea induced hypoglycemia the very long half-life of these
substances must be considered as patients may show relapsing hypo-
glycemia for more than 24 h even after glucose substitution. Considering
the risk of hypoglycemia, on principle, and the increased risk of
hypoglycemia with sulfonylurea therapy in case of renal dysfunction, the
use of sulfonylureas in the treatment of type II diabetes is currently under
discussion (Inzucchi et al. 2015).
Hypoglycemia is a medical emergency and should be treated in case of
severe neurological symptoms with parenteral application of glucose
(20-50 ml of 40% glucose) – if needed repeatedly.
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Hyperglycemia
Hyperglycemic emergencies - diabetic ketoacidosis (DKA) and nonketotic
hyperosmolar coma (also called hyperosmolar hyperglycemic state (HHS)) –
are rare in a neurological emergency unit. Diabetic ketoacidosis pre-
dominantly affects patients with type I diabetes, and may even be the
first manifestation of the disease. DKA is an insulin-deficient state, thus
insulin application is the cornerstone of therapy. Replacing fluid and
electrolytes is also required since with increased blood glucose levels
finally glucosuria and a forced osmotic diuresis ensue. Patients usually
need 7-10 l fluid replacement over the first 24 h of therapy, starting with
about 1 l/h over the first 3 hours. Insulin substitution includes a bolus of
10-20 International Units (IU) of regular insulin followed by continuous
intravenous application of 5-10 IU/h. Blood glucose levels need to be
monitored during the therapy and should not decrease more than 50
mg/dl/h, otherwise the patients are at risk to develop brain edema. In
addition to blood glucose levels also electrolyte levels must be closely
monitored, as potassium levels may substantially decrease with ongoing
insulin and fluid therapy. The treatment goal is to maintain serum
potassium levels within the normal range of 4–5 mEq/l.
Involvement of a neurologist in the treatment of a patient with severe
hyperglycemia is more likely in HHS than in DKA. Alterations of conscious-
ness, seizures and focal neurological deficits are more frequent in patients
with HHS than in DKA. Of note, stroke might accompany HHS, either as a
complication due to the procoagulant status or as precipitant. Available
evidence suggests that hyperglycemic emergencies are associated with an
inflammatory and procoagulant state, which both contribute to an
increased risk of thrombotic complications. Thus, heparin should be
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administered subcutaneously for prophylaxis of thrombosis. A protocol for
the treatment of adult patients with DKA or hyperosmolar hyperglycemic
state is given for example in Katabchi et al. (2009)
Two characteristic, though rare, complications of HHS are epilepsia
partialis continua (Kojewnikow) and hemichorea. The latter is
accompanied with characteristic CCT and MRI signal alterations in the
contralateral striatum, and may persist for several days after the
normalization of blood glucose levels (Kandiah et al. 2009).
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