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: Weissenborn.Karin@mh-hannover.de

1

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

2

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

3

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.

4

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

5

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

6

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

7

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

8

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).

9

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.

10

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.

11

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

12

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).

13

References

1. Acharya SK, Bhatia V, Sreenivas V, et al. Efficacy of L-ornithine

L-aspartate in acute liver failure: a double-blind, randomized,

placebo-controlled study. Gastroenterology 136:2159, 2009

2. Bass NM, Mullen KD, Sanyal A, Poordad F, Neff G, Leevy CB, Sigal S,

et al. (2010) Rifaximin treatment in hepatic encephalopathy. N

Engl J Med.; 362(12):1071-81

3. Brouns R, De Deyn PP (2004); Neurological complications in renal

failure: a review. Clin Neurol Neurosurg 107(1), 1-16

4. Cardoso FS, Marcelino P, Bagulho L, Karvellas CJ. (2017) Acute liver

failure: An up-to-date approach. J Crit Care; 19; 39:25-30

5. Fabiani G, Teive HA, Munhoz RP (2013) Lentiform fork sign and

fluctuating, reversible parkinsonism in a patient with uremic

encephalopathy. Mov Disord ; 28(8):1053

6. Hung SC, Hung SH, Tarng DC, Yang WC, Chen TW, Huang TP. (2001)

Thiamine deficiency and unexplained encephalopathy in

hemodialysis and peritoneal dialysis patients. Am J Kidney

Dis;38(5):941-7

7. Ihara M, Ito T, Yanagihara C, Nishimura Y. (1999) Wernicke's

encephalopathy associated with hemodialysis: report of two cases

and review of the literature. Clin Neurol Neurosurg;101(2):118-21

8. Inzucchi SE, Bergenstal RM, Buse JB et al (2015) Management of

hyperglycaemia in type 2 diabetes, 2015: a patient-centred

approach. Update to a position statement of the American Diabetes

Association and the European Association for the Study of Diabetes.

Diabetologia 58:429–442

9. Jones EA, Weissenborn K (1997); Neurology and the Liver. J Neurol

Neurosurg Psychiatry 63(3): 279–293

10. Kandiah N, Tan K, Lim CCT, Venketasubramanian N (2009)

Hyperglycemic choreoathetosis. Movement Disorders 24(6): 915–936

11. Karvellas CJ, Fix OK, Battenhouse H, et al. (2014) Outcomes and

complications of intracranial pressure monitoring in acute liver

failure: a retrospective cohort study. Crit Care Med;42:1157–1167.

12. Katoh M, Yoshino M, Aoki T, Abumiya T, Imamura H, Aida T. (2016)

Localized reversible high signal intensities on diffusion-weighted

MRI in hypoglycemia: A study of 70 cases. Asian J Neurosurg;

11(4):412-415

13. Kim DM, Lee IH, Song CJ. (2016) Uremic Encephalopathy: MR

Imaging Findings and Clinical Correlation. AJNR Am J Neuroradiol.;

37(9):1604-9

14

14. Kircheis G, Nilius R, Held C et al. (1997) Therapeutic efficacy of

L-ornithine-L-aspartate infusions in patients with cirrhosis and

hepatic encephalopathy: Results of a placebo-controlled, double-

blind study. Hepatology 25: 1351–1360

15. Kitabchi AE, Umpierrez GE, Miles JM, Fisher JN (2009) Hyper-

glycemic crises in adult patients with diabetes. Diabetes Care

32(7): 1335–1343

16. Kumar G, Goyal MK. (2010) Lentiform Fork sign: a unique MRI

picture. Is metabolic acidosis responsible? Clin Neurol

Neurosurg;112(9):805-12

17. Lee WM, Larson AM, Stravitz RT. AASLD Position Paper:

The management of acute liver failure: Update 2011.

www.aasld.org, 2011

18. Morgan MY (1998); Cerebral magnetic resonance imaging in

patients with chronic liver disease. Met Brain Dis 13(4): 273-290

19. O'Grady JG, Alexander GJ, Hayllar KM, Williams R. (1989) Early

indicators of prognosis in fulminant hepatic failure.

Gastroenterology;97(2):439-45

20. Penin H (1967) Über den diagnostischen Wert des Hirnstrombildes

bei der hepato-portalen Encephalopathie. Fortschr Neurol Psychiatr

Grenzgeb 35: 174–234

21. Plum F, Posner JB (1982); The diagnosis of stupor and coma,

3rd edn. Davis, Philadelphia, pp 1–86

22. Rose C, Butterworth RF, Zayed J et al. (1999) Manganese

deposition in basal ganglia structures results from both portal-

systemic shunting and liver dysfunction. Gastroenterology

117(3): 640–644

23. Schomerus H, Hamster W (2001) Quality of life in cirrhotics with

minimal hepatic encephalopathy. Metab Brain Dis 16: 13–19

24. Seifter JL, Samuels MA (2011); Uremic encephalopathy and other

brain disorders associated with renal failure. Semin Neurol

31(2):139-143

25. Sherlock S, Summerskill WH, White LP, Phear EA. (1954) Portal-

systemic encephalopathy; neurological complications of liver

disease. Lancet; 267(6836):454-7.

26. Summerskill WH, Davidson EA, Sherlock S, Steiner RE. (1956) The

neuropsychiatric syndrome associated with hepatic cirrhosis and an

extensive portal collateral circulation. Q J Med.;25(98):245-66

15

27. Vilstrup H, Amodio P, Bajaj J, Cordoba J, Ferenci P, Mullen KD,

Weissenborn K, Wong P. (2014) Hepatic encephalopathy in chronic

liver disease: 2014 Practice Guideline by the American Association

for the Study of Liver Diseases and the European Association for the

Study of the Liver. Hepatology ;60(2):715-35

28. Weissenborn K. (2014) Hepatic and pancreatic encephalopathy. In:

Aminoff’s Neurology and General Medicine, 5th edition (Eds.

Aminoff MJ, Josephson SA); Academic Press, pp223-236

29. Weissenborn K, Lockwood AH. (2015) Metabolic and toxic

encephalopathies. In: Bradley's Neurology in Clinical Practice, 7th

edition (Eds. Daroff R, Jankovic J, Mazziotta J, Pomeroy S);

Elsevier, chapter 84

30. Weissenborn K. (2015) The Clinical Relevance of Minimal Hepatic

Encephalopathy--A Critical Look. Dig Dis. 2015;33(4):555-61.