This clinical syndrome is seen in 0.3% of cancer patients (Nath & Grant, 1997). Patients tend to be of middle age with no sex predilection. Patients develop mood and sleep disturbances, seizures, hallucinations and short term memory loss. This cognitive decline can eventually lead towards dementia (Voltz, 2002).

Electro-encephalographic findings often include epileptic foci, mostly in one or both temporal lobes, next to generalized slow wave activity. In 70 to 80% of patients, hyperintense foci in the medial part of one or both temporal lobes are seen on MRI fluidattenuated inversion recovery (FLAIR) and T2-weighted sequences. Gadolinium contrast enhanced lesions are rare. Fluoro-deoxy-glucose PET often shows hypermetabolism of the medial parts of the temporal lobes and often precedes MRI findings. In cerebrospinal fluid, findings suggest inflammation (Gozzard & Maddison, 2010).

Differential diagnoses of limbic encephalitis include viral encephalitis, prion diseases and auto-immune non-neoplastic encephalopathies (Voltz, 2002).

Neuropathological findings can be summarized as an inflammation of the structures of the limbic system. Perivascular lymphocytic infiltration is seen, in combination with microglial proliferation and reactive gliosis. Immunological staining with anti-Hu shows strong staining of neuronal nuclei in central and peripheral nervous tissue with sparing of nucleoli. Cytoplasm is weakly stained. There is no staining of systemic tissue (Nath & Grant, 1997).

Tumours most frequently involved are SCLC, testicular germ-cell malignancies, thymoma, teratoma or Hodgkin's lymphoma. Dependent on the antibody which is found in serum and cerebrospinal fluid, subtyping of limbic encephalitis is recommended (Dalmau & Rosenfield, 2008).

Anti-NMDA receptor antibodies and anti-VGKC antibodies act against proteins that are exposed on the cell surface from e.g. hippocampus. Patients with a positive serology for those antibodies, respond well to immunotherapy, whereas patients who are positive for antibodies acting against antigens localised on the cytoplasmatic side of the cell (e.g. amphiphysin) or localised in the cytoplasm or nucleus (e.g. GAD, Hu), respond less or not to immunotherapy.

Limbic encephalitis with antibodies to intracellular antigens

In about 1 of 2 patients with anti-Hu antibodies SCLC and limbic encephalitis, the clinical picture starts with the symptomatology of limbic encephalitis but evolves eventually into a more widespread encephalitis, often in combination with myelitis.

Patients can present with anti-CRMP5 (anti-CV2) antibodies. In those cases, the clinical picture can be dominated by optic neuritis and myelitis, whereas symptoms suggestive of

CSF studies may show pleocytosis and elevated protein levels. MRI brain scans are mostly normal. However, hyperintense T2-weighted lesions in brainstem, thalamus and

Extensive neuronal loss is seen in the affected brain regions: hippocampal sclerosis, gliosis

This clinical syndrome is seen in 0.3% of cancer patients (Nath & Grant, 1997). Patients tend to be of middle age with no sex predilection. Patients develop mood and sleep disturbances, seizures, hallucinations and short term memory loss. This cognitive decline can eventually

Electro-encephalographic findings often include epileptic foci, mostly in one or both temporal lobes, next to generalized slow wave activity. In 70 to 80% of patients, hyperintense foci in the medial part of one or both temporal lobes are seen on MRI fluidattenuated inversion recovery (FLAIR) and T2-weighted sequences. Gadolinium contrast enhanced lesions are rare. Fluoro-deoxy-glucose PET often shows hypermetabolism of the medial parts of the temporal lobes and often precedes MRI findings. In cerebrospinal fluid,

Differential diagnoses of limbic encephalitis include viral encephalitis, prion diseases and

Neuropathological findings can be summarized as an inflammation of the structures of the limbic system. Perivascular lymphocytic infiltration is seen, in combination with microglial proliferation and reactive gliosis. Immunological staining with anti-Hu shows strong staining of neuronal nuclei in central and peripheral nervous tissue with sparing of nucleoli. Cytoplasm is weakly stained. There is no staining of systemic tissue (Nath & Grant, 1997). Tumours most frequently involved are SCLC, testicular germ-cell malignancies, thymoma, teratoma or Hodgkin's lymphoma. Dependent on the antibody which is found in serum and cerebrospinal fluid, subtyping of limbic encephalitis is recommended (Dalmau &

Anti-NMDA receptor antibodies and anti-VGKC antibodies act against proteins that are exposed on the cell surface from e.g. hippocampus. Patients with a positive serology for those antibodies, respond well to immunotherapy, whereas patients who are positive for antibodies acting against antigens localised on the cytoplasmatic side of the cell (e.g. amphiphysin) or localised in the cytoplasm or nucleus (e.g. GAD, Hu), respond less or not

In about 1 of 2 patients with anti-Hu antibodies SCLC and limbic encephalitis, the clinical picture starts with the symptomatology of limbic encephalitis but evolves eventually into a

Patients can present with anti-CRMP5 (anti-CV2) antibodies. In those cases, the clinical picture can be dominated by optic neuritis and myelitis, whereas symptoms suggestive of

hippocampus can be seen. Lesions are rarely contrast enhancing.

findings suggest inflammation (Gozzard & Maddison, 2010).

auto-immune non-neoplastic encephalopathies (Voltz, 2002).

Limbic encephalitis with antibodies to intracellular antigens

more widespread encephalitis, often in combination with myelitis.

in brainstem, spinal cord and dorsal root ganglia.

**2.3.3 Paraneoplastic limbic encephalitis**

lead towards dementia (Voltz, 2002).

Rosenfield, 2008).

to immunotherapy.

encephalitis are less explicit. SCLC and thymoma are tumours most commonly involved. The combination of optic neuritis and myelitis resembles a diagnosis of Devic's syndrome (neuromyelitis optica).

Anti-Ma2 antibodies are associated with limbic encephalitis in combination with involvement of the hypothalamus and brainstem. Clinical presentation is variable and can start with hypersomnolence, cataplexy, narcolepsy, REM sleep disturbances, hormonal deficits or hyperphagia. Involvement of the mesencephalon causes vertical gaze palsy, orofacial and jaw dystonia. Differential diagnosis has to be made with Whipple's disease.

Anti-Ma2 antibodies in males younger than 50 years should trigger a screening program for testicular germ-cell tumours. In older patients, SCLC or breast tumours have to be excluded.

Many patients with germ-cell tumours of the testes and anti-Ma2-associated encephalitis benefit from orchiectomy and immunotherapy. In 35% of patients, neurological signs improve.

Limbic encephalitis with antibodies to neuronal cell-surface antigens

The two main clinical syndromes associated with these antibodies are typical limbic encephalitis and encephalitis with psychiatric symptoms, hallucinations and peripheral nerve hyperexcitability, amongst other signs of autonomic dysfunction.

Antibodies act against the voltage-gated potassium channels.

About 30% of patients with anti-VGKC antibodies have tumours, of which SCLC and thymoma are most prevalent.

The CSF of those patients shows less inflammation, less pleiocytosis and lower protein concentration compared to other PNS.

80% of patients respond to immunotherapy.

Patients with anti-NMDA-receptor antibodies are usually young and female. Symptomatology starts with headaches, memory deficits, epileptic seizures and psychiatric behavioural symptoms. As the disease progresses, autonomic disturbances are seen, leading to supported ventilation or pace-making.

About 65% of the patients have a malignancy. Underlying tumour is mostly a (cystic) ovarian teratoma. Immunotherapy in combination with treatment of the tumour results mostly in neurological improvement.

#### **2.3.4 Paraneoplastic opsoclonus-myoclonus-ataxia syndrome**

Opsoclonus is the abnormal movement of the eyes consisting of chaotic, involuntary conjugated saccades with horizontal, vertical and torsional components and without intersaccadic interval. Myoclonus is most often present as myoclonic jerks in limbs and trunk. Occasionally, encephalopathy or cerebellar ataxia is present.

Clinical symptoms often have an acute onset and may fluctuate in the development of the PNS. Rarely, it resolves spontaneously.

Opsoclonus-myoclonus-ataxia syndrome can occur in combination with infections, metabolic disturbances, toxic factors as well as in combination with neoplasm.

Neoplasm Related Encephalopathies 105

and excessive production of certain hormones or proteins, elicited by cancer or not. Some specific clinical entities have been described. Neuro-endocrine tumours can synthesize biologically active substances, such as hormones, growth factors or cytokines, which can induce non-immune mediated encephalopathy. For instance, pheochromocytoma, paraganglioma or tumours of the adrenal gland can cause hypertensive encephalopathy

A peculiar form of non-immune mediated encephalopathy has been described in carcinoid tumours where competition arises between the tumour and the nervous tissue for a specific substance called tryptophan. Active production of serotonin by the carcinoid tumour causes depletion of tryptophan leading to neuronal dysfunction. Associated neurological disorders include carcinoid myopathy and carcinoid encephalopathy. Other mechanisms of carcinoid encephalopathy have also been proposed such as excessive production of serotonin in the brain by CNS metastasis, fulminant hepatic metastasis and aberrant secretion of ACTH of CRH by carcinoid tumours (Lapeire et al., 2010). Treatment of carcinoid encephalopathy is mainly focused on controlling the tumour although more 'targeted' treatment such as oral tryptophan substitution or serotonin receptor antagonism have proved their use in case

As the treatment modalities of cancer evolve, the side effects subsequently follow. Already decades ago, cytotoxic agents were linked with the development of encephalopathies and with the more recently developed targeted therapies the number of case reports regarding

Cancer treatment related encephalopathies can be divided into two groups. On one hand we have toxic encephalopathies, of which posterior reversible encephalopathy syndrome or PRES is an uncommon yet characteristic cliniconeuroradiological syndrome. The second group comprises encephalopathies induced by opportunistic infections with progressive

In 1996, Hinchey et al. were the first to describe a syndrome characterized by similar cliniconeuroradiological findings in a group of patients with different clinical settings (Hinchey et al., 1996). They suggested the term 'reversible posterior leukoencephalopathy syndrome' (RPLS) given the reversibility of the abnormalities and the typical localization of

Afterwards, many critical remarks were postulated on the term RPLS. First of all, some case reports described the development of intracranial hemorrhage as complication with subsequent permanent sequellae or even fatal outcome, suggesting that not all RPLS are 'reversible' (Schwartz, 1996). Secondly, although in most patients the posterior regions were involved, other brain regions were also often affected. Thirdly, the term leukoencephalopathy is too restrictive since the white-matter lesions were frequently

multifocal leukoencephalopathy or PML being most reported and investigated.

white-matter lesions in the posterior occipital-parietal regions of the brain.

**3.1 Posterior reversible encephalopathy syndrome (PRES)**

through production of vaso-active peptides (Kaltsas et al., 2010).

**3. Cancer treatment related encephalopathies**

cancer treatment related encephalopathies is rising.

**3.1.1 Definition of PRES**

accompanied with cortical involvement.

reports.

MRI is usually normal. CSF may show mild inflammatory changes, mostly B-lymphocyte pleiocytosis and oligoclonal bands (Gozzard & Maddison, 2010). EEG may be normal or demonstrate generalized slow activity, without epileptic discharges.

Paraneoplastic opsoclonus-myoclonus-ataxia syndrome is seen in 3 patients groups.

In children, this clinical syndrome is seen in combination with neuroblastoma in 50% of cases. There is no corresponding antibody identified.

In adult female patients, the tumour most commonly found is cancer of ovary and breast. The associated antibody is anti-Ri.

In adult patients who are anti-Ri antibody negative, the underling tumour is SCLC. A positive serology for anti-Hu and an association with anti-Ma2 has been described in patients with SCLC and opsoclonus-myoclonus-ataxia syndrome (Voltz, 2002).

Recent immunological findings however have demonstrated the presence of antibodies against postsynaptic or cell-surface antigens. Those antibodies, present in the serum of children with neuroblastoma, react with the cell surfaces of cerebellar granular neurons and neuroblastoma cells (Dalmau et al, 2007).

Neuropathology shows a mild perivascular and interstitial lymphocytic infiltration, in combination with a relative loss of Purkinje cells and loss of neurons in the dentate nucleus.

Immunhistochemistry pattern of anti-Ri include strong staining of only central nervous system neuronal tissue, sparing of nucleoli, weak cytoplasmatic staining and no staining of systemic tissues (Nath & Grant, 1997; PNS Euronetwork, 2002).

#### **2.4 Treatment of PNS**

There is no standard of care for PNS of the central nervous system. Moreover, in the vast majority of cases, PNS are refractory to any form of treatment.

Clinical experience suggests that treatment and removal of the causing factor, i.e. the tumour is necessary to stabilise or improve symptomatology. Adjuvant corticosteroids, intravenous immunoglobulin therapy, plasma exchange, cyclophosphamide and tacrolimus have not substantially improved the neurological outcome.(Dalmau & Rosenfield, 2008).

In children with paraneoplastic opsoclonus-myoclonus syndrome, the clinical picture often responds, however only partially, to treatments such as corticosteroids, intravenous immunoglobulin, plasma exchange, cyclophosphamide or rituximab. Symptom relapses can occur during transient illnesses (e.g. viral infections). In adults, paraneoplastic opsoclonusmyoclonus syndrome is less responsive to immunotherapy. Stabilisation or improvement is only seen in patients with cured or controlled malignancies. Rarely, spontaneous remission of neurological symptoms can occur in patients with opsoclonus-myoclonus-ataxia syndrome. (Nath & Grant, 1997).

#### **2.5 Non-immune mediated paraneoplastic encephalopathies**

As previously mentioned, non-immune mediated encephalopathies can be provoked by a whole spectrum of etiological factors such as metabolic disorders, electrolyte disturbances

MRI is usually normal. CSF may show mild inflammatory changes, mostly B-lymphocyte pleiocytosis and oligoclonal bands (Gozzard & Maddison, 2010). EEG may be normal or

In children, this clinical syndrome is seen in combination with neuroblastoma in 50% of

In adult female patients, the tumour most commonly found is cancer of ovary and breast.

In adult patients who are anti-Ri antibody negative, the underling tumour is SCLC. A positive serology for anti-Hu and an association with anti-Ma2 has been described in

Recent immunological findings however have demonstrated the presence of antibodies against postsynaptic or cell-surface antigens. Those antibodies, present in the serum of children with neuroblastoma, react with the cell surfaces of cerebellar granular neurons and

Neuropathology shows a mild perivascular and interstitial lymphocytic infiltration, in combination with a relative loss of Purkinje cells and loss of neurons in the dentate nucleus. Immunhistochemistry pattern of anti-Ri include strong staining of only central nervous system neuronal tissue, sparing of nucleoli, weak cytoplasmatic staining and no staining of

There is no standard of care for PNS of the central nervous system. Moreover, in the vast

Clinical experience suggests that treatment and removal of the causing factor, i.e. the tumour is necessary to stabilise or improve symptomatology. Adjuvant corticosteroids, intravenous immunoglobulin therapy, plasma exchange, cyclophosphamide and tacrolimus have not substantially improved the neurological outcome.(Dalmau & Rosenfield, 2008).

In children with paraneoplastic opsoclonus-myoclonus syndrome, the clinical picture often responds, however only partially, to treatments such as corticosteroids, intravenous immunoglobulin, plasma exchange, cyclophosphamide or rituximab. Symptom relapses can occur during transient illnesses (e.g. viral infections). In adults, paraneoplastic opsoclonusmyoclonus syndrome is less responsive to immunotherapy. Stabilisation or improvement is only seen in patients with cured or controlled malignancies. Rarely, spontaneous remission of neurological symptoms can occur in patients with opsoclonus-myoclonus-ataxia

As previously mentioned, non-immune mediated encephalopathies can be provoked by a whole spectrum of etiological factors such as metabolic disorders, electrolyte disturbances

Paraneoplastic opsoclonus-myoclonus-ataxia syndrome is seen in 3 patients groups.

patients with SCLC and opsoclonus-myoclonus-ataxia syndrome (Voltz, 2002).

systemic tissues (Nath & Grant, 1997; PNS Euronetwork, 2002).

majority of cases, PNS are refractory to any form of treatment.

**2.5 Non-immune mediated paraneoplastic encephalopathies**

demonstrate generalized slow activity, without epileptic discharges.

cases. There is no corresponding antibody identified.

The associated antibody is anti-Ri.

neuroblastoma cells (Dalmau et al, 2007).

**2.4 Treatment of PNS**

syndrome. (Nath & Grant, 1997).

and excessive production of certain hormones or proteins, elicited by cancer or not. Some specific clinical entities have been described. Neuro-endocrine tumours can synthesize biologically active substances, such as hormones, growth factors or cytokines, which can induce non-immune mediated encephalopathy. For instance, pheochromocytoma, paraganglioma or tumours of the adrenal gland can cause hypertensive encephalopathy through production of vaso-active peptides (Kaltsas et al., 2010).

A peculiar form of non-immune mediated encephalopathy has been described in carcinoid tumours where competition arises between the tumour and the nervous tissue for a specific substance called tryptophan. Active production of serotonin by the carcinoid tumour causes depletion of tryptophan leading to neuronal dysfunction. Associated neurological disorders include carcinoid myopathy and carcinoid encephalopathy. Other mechanisms of carcinoid encephalopathy have also been proposed such as excessive production of serotonin in the brain by CNS metastasis, fulminant hepatic metastasis and aberrant secretion of ACTH of CRH by carcinoid tumours (Lapeire et al., 2010). Treatment of carcinoid encephalopathy is mainly focused on controlling the tumour although more 'targeted' treatment such as oral tryptophan substitution or serotonin receptor antagonism have proved their use in case reports.

#### **3. Cancer treatment related encephalopathies**

As the treatment modalities of cancer evolve, the side effects subsequently follow. Already decades ago, cytotoxic agents were linked with the development of encephalopathies and with the more recently developed targeted therapies the number of case reports regarding cancer treatment related encephalopathies is rising.

Cancer treatment related encephalopathies can be divided into two groups. On one hand we have toxic encephalopathies, of which posterior reversible encephalopathy syndrome or PRES is an uncommon yet characteristic cliniconeuroradiological syndrome. The second group comprises encephalopathies induced by opportunistic infections with progressive multifocal leukoencephalopathy or PML being most reported and investigated.

#### **3.1 Posterior reversible encephalopathy syndrome (PRES)**

#### **3.1.1 Definition of PRES**

In 1996, Hinchey et al. were the first to describe a syndrome characterized by similar cliniconeuroradiological findings in a group of patients with different clinical settings (Hinchey et al., 1996). They suggested the term 'reversible posterior leukoencephalopathy syndrome' (RPLS) given the reversibility of the abnormalities and the typical localization of white-matter lesions in the posterior occipital-parietal regions of the brain.

Afterwards, many critical remarks were postulated on the term RPLS. First of all, some case reports described the development of intracranial hemorrhage as complication with subsequent permanent sequellae or even fatal outcome, suggesting that not all RPLS are 'reversible' (Schwartz, 1996). Secondly, although in most patients the posterior regions were involved, other brain regions were also often affected. Thirdly, the term leukoencephalopathy is too restrictive since the white-matter lesions were frequently accompanied with cortical involvement.

Neoplasm Related Encephalopathies 107

The name PRES was given to common cliniconeuroradiological findings in patients with very divergent underlying pathologies as summarized in table 6. All these clinical conditions induce a form of 'systemic toxicity', making the patient vulnerable for

With regard to cancer treatment, PRES was mostly seen after the administration of highdose (combination) chemotherapy for hematologic malignancies. However, PRES has also been reported in patients treated with a single chemotherapeutic agent like cisplatin, gemcitabine or cytarabine. Moreover, the newer 'targeted therapies' like the monoclonal antibody bevacizumab and the tyrosine kinase inhibitors sorafenib and vandetanib have recently been linked with the development of PRES (Broniscer et al., 2010; Glusker et al.,

**3.1.3 Etiology**

developing PRES.

Frequently:

2006; Govindarajan et al., 2006).

 Preeclampsia/eclampsia Infection/sepsis/shock

disease, etc.)

Miscellaneous (not limited): Hypomagnesemia Hypercalcemia Hypocholesterolemia

 Intravenous immunoglobulin Guillain-Barré syndrome Ephedra overdose Tumor lysis syndrome Triple-H therapy Hydrogen peroxide

 Dimethyl sulfoxide stem cells Dislysis/erythropoietin Corticosteroid treatment

**3.1.4 Pathophysiology**

Table 6. Clinical conditions associated with PRES

**Clinical conditions associated with PRES**

Post-transplantation (allo-BMT, solid organ transplantation)

 Cancer therapy (combination chemotherapy, single agent, targeted therapy) Auto-immune diseases (systemic lupus erythematosus, scleroderma, Wegener's

The pathophysiological mechanism behind PRES still remains a matter of debate.

leading to reduced blood flow, ischemia and subsequent vasogenic edema.

When PRES was initially described, the hypodense parietal-occipital regions on CT imaging prompted investigators to suggest that ischemia was the causative factor of the observed abnormalities. The hypothesis was that the 'systemic disease' of the patient elevates the blood pressure which is counteracted by an auto-regulatory vasoconstriction in the brain,

Immune suppression (cyclosporine, tacrolimus)

Since then, many other therms were proposed like 'hypertension encephalopathy' (HTE), 'occipito-parietal encephalopathy' (Pavlakis et al., 1997) or 'potentially reversible encephalopathy syndrome' (Narbone et al., 2006). Casey et al. first used the term 'posterior reversible encephalopathy syndrome' or PRES (Casey et al., 2000). Although 'posterior' and 'reversible' are still present, the term PRES became generally accepted and systematically used. A possible explanation for this acceptance is that in time, it became apparent that with a prompt diagnosis and treatment, PRES is reversible in almost every patient. In addition, using the term 'posterior' does not exclude other regions to be involved but merely depicts the fact that occipito-parietal abnormalities are the most common feature on neuro-imaging.

#### **3.1.2 Clinical presentation**

PRES normally emerges gradually over a few days but can also have an acute, sudden onset. Mild to severe hypertension is a common feature in 70 to 80% of patients with PRES. Other typical clinical symptoms include headache, nausea/vomiting, seizures and visual disturbances (table 5). Seizures may start focally and evolve into generalized attacks or even status epilepticus. Quite often, seizures are the first presenting symptom of PRES. Many forms of visual changes have been reported ranging from a blurred vision to complete cortical blindness.

Next to the typical symptoms, many patients with PRES suffer from an altered mental status with confusion and diminished concentrating ability. Lethargy is common, sometimes worsening into stupor or even coma. Other neurological aberrations, like dysarthria and ataxia, have also been associated with PRES.

Table 5. Clinical symptoms of PRES

#### **3.1.3 Etiology**

106 Miscellanea on Encephalopathies – A Second Look

Since then, many other therms were proposed like 'hypertension encephalopathy' (HTE), 'occipito-parietal encephalopathy' (Pavlakis et al., 1997) or 'potentially reversible encephalopathy syndrome' (Narbone et al., 2006). Casey et al. first used the term 'posterior reversible encephalopathy syndrome' or PRES (Casey et al., 2000). Although 'posterior' and 'reversible' are still present, the term PRES became generally accepted and systematically used. A possible explanation for this acceptance is that in time, it became apparent that with a prompt diagnosis and treatment, PRES is reversible in almost every patient. In addition, using the term 'posterior' does not exclude other regions to be involved but merely depicts the fact that occipito-parietal abnormalities are the most common feature on neuro-imaging.

PRES normally emerges gradually over a few days but can also have an acute, sudden onset. Mild to severe hypertension is a common feature in 70 to 80% of patients with PRES. Other typical clinical symptoms include headache, nausea/vomiting, seizures and visual disturbances (table 5). Seizures may start focally and evolve into generalized attacks or even status epilepticus. Quite often, seizures are the first presenting symptom of PRES. Many forms of visual changes have been reported ranging from a blurred vision to complete

Next to the typical symptoms, many patients with PRES suffer from an altered mental status with confusion and diminished concentrating ability. Lethargy is common, sometimes worsening into stupor or even coma. Other neurological aberrations, like dysarthria and

> Tonic-clonic/generalized Status epilepticus

**Clinical symptoms of PRES**

Hypertension Headache

Seizures

Nausea/vomiting

Focal

Visual disturbances

Blurred vision Hemianopsy Visual neglect Cortical blindness

**3.1.2 Clinical presentation**

ataxia, have also been associated with PRES.

Typical:

Other:

Table 5. Clinical symptoms of PRES

Confusion Attention deficit Lethargy Stupor Coma Ataxia Dysarthria

cortical blindness.

The name PRES was given to common cliniconeuroradiological findings in patients with very divergent underlying pathologies as summarized in table 6. All these clinical conditions induce a form of 'systemic toxicity', making the patient vulnerable for developing PRES.

With regard to cancer treatment, PRES was mostly seen after the administration of highdose (combination) chemotherapy for hematologic malignancies. However, PRES has also been reported in patients treated with a single chemotherapeutic agent like cisplatin, gemcitabine or cytarabine. Moreover, the newer 'targeted therapies' like the monoclonal antibody bevacizumab and the tyrosine kinase inhibitors sorafenib and vandetanib have recently been linked with the development of PRES (Broniscer et al., 2010; Glusker et al., 2006; Govindarajan et al., 2006).

#### **Clinical conditions associated with PRES**

Frequently: Preeclampsia/eclampsia Infection/sepsis/shock Post-transplantation (allo-BMT, solid organ transplantation) Immune suppression (cyclosporine, tacrolimus) Cancer therapy (combination chemotherapy, single agent, targeted therapy) Auto-immune diseases (systemic lupus erythematosus, scleroderma, Wegener's disease, etc.)

Miscellaneous (not limited):

 Hypomagnesemia Hypercalcemia Hypocholesterolemia Intravenous immunoglobulin Guillain-Barré syndrome Ephedra overdose Tumor lysis syndrome Triple-H therapy Hydrogen peroxide Dimethyl sulfoxide stem cells Dislysis/erythropoietin Corticosteroid treatment

Table 6. Clinical conditions associated with PRES

#### **3.1.4 Pathophysiology**

The pathophysiological mechanism behind PRES still remains a matter of debate.

When PRES was initially described, the hypodense parietal-occipital regions on CT imaging prompted investigators to suggest that ischemia was the causative factor of the observed abnormalities. The hypothesis was that the 'systemic disease' of the patient elevates the blood pressure which is counteracted by an auto-regulatory vasoconstriction in the brain, leading to reduced blood flow, ischemia and subsequent vasogenic edema.

Neoplasm Related Encephalopathies 109

and a dominant parietal-occipital pattern. These three typical patterns were seen in 99 of 136 patients with PRES. The other patients showed a partial or asymmetric variation of one of these major patterns (Bartynski and Boardman, 2007). Awareness of these different patterns is of great importance for a quick diagnosis and treatment, subsequently leading towards a

Picture 1. An example of NMR imaging in PRES: hyperintense signal (white arrowheads) on T2-weighted (left) and FLAIR (right) images of symmetrical affected parieto-occipital

MR diffusion weighted imaging (DWI) with calculation of the apparent diffusion coefficient (ADC) may have an additional value in distinguishing a vasogenic edema (in PRES) from a cytotoxic edema (infarction), especially given the differences in treatment strategies

Cerebral angiography (CA) and MR angiography (MRA) commonly show signs of diffuse or focal vasoconstriction (with sometimes a typical string-of-beads appearance) and vasculopathy (Bartynski and Boardman, 2008). MR perfusion mostly reveals a reduced

MR spectroscopy describes reduced N-acetylaspartate:choline and N-acetylaspartate: creatinine ratios suggesting neuronal, axonal or synaptic dysfunction (Bartynski, 2008a; Pavlakis, 1997; Staykov and Schwab, 2011). The presence of lactate in PRES accompanied by vasoconstriction is suggestive for ischemia (Bartynski, 2008a; Staykov and Schwab, 2011). It is clear that information and results obtained from the more recent and advanced imaging techniques like CA, MRA, MR perfusion and others are more in favor of the old

blood flow in the affected areas (Bartynski, 2008a; Brubaker et al., 2005).

better outcome.

regions.

(Doelken, 2007).

vasoconstriction/hypoperfusion theory.

As more cases were described and more research was performed, a new hypothesis was proposed based upon the hypertension/hyperperfusion theory. This hypothesis stated that PRES was the result of acute and severe hypertension beyond the autoregulatory limits, leading to a breakthrough of the blood-brain barrier, hyperperfusion, capillary bed injury, fluid leakage and vasogenic edema (Bartynski, 2008b, Staykov and Schwab, 2011). Different animal studies supporting the hypertension/hyperperfusion theory and the success of immediate anti-hypertensive treatment in clinical setting strengthened the belief in this more recent hypothesis.

However, several remarks have been posted questioning the reliability of this mechanism. For instance, hypertension is not or only mildly present in about 25% of patients with PRES, certainly not reaching the upper limits of autoregulation (Bartynski, 2008b, Staykov and Schwab, 2011). Secondly, solid evidence of hyperperfusion is scarce. Thirdly, the results from animal studies can not merely be extrapolated to humans. In patients with PRES, hypertension is induced by a 'systemic process/disease' while in animal studies hypertension is induced in healthy animals (Bartynski, 2008b and Staykov, 2011). At last, more advanced imaging techniques like cerebral angiography and MR angiography showed unexpectedly an inverse relation between the severity of hypertension and the extent of brain edema (Bartynski and Boardman, 2008).

In addition, as our knowledge of PRES expands, new insights in the pathophysiological mechanisms arise, pointing towards the older vasoconstriction-hypoperfusion theory. For example, all the well-known underlying pathologies (table 6) show activation of the cellular immune system, production of inflammatory cytokines and endothelial activation and injury, leading to a vasculopathy with vasoconstriction, hypoperfusion and subsequent ischemia as possible outcome (Bartynski, 2008b). It is clear that more investigations in this area are needed to elucidate this complex subject.

#### **3.1.5 Diagnosis**

The diagnosis of PRES is mainly based upon the combination of typical clinical symptoms and specific abnormalities on brain imaging.

A laboratory work-out can give an indirect hint towards PRES by detecting thrombocytopenia, schistocytes and an increased serum lactate dehydrogenase (LDH) caused by endothelial injury which almost always accompanies PRES (Bartynski, 2008a; Staykov and Schwab, 2011).

Affected brain regions can be recognized by a hypodense signal on CT-scan but an MRI of the brain with fluid–attenuated inversion recovery (FLAIR) is the gold standard for the diagnosis of PRES because of its higher accuracy in detecting all affected areas (Casey et al., 2000). A pattern of symmetrical edema of the parietal-occipital regions is most frequently seen on neuro-imaging (Picture 1), but involvement of the frontal lobes, basal ganglia, brain stem and cerebellum have also been reported (Bartynski, 2008a; Hinchey et al., 1996; Staykov and Schwab, 2011).

Focal aberrations can be present along with the symmetrical edema but in absence of the latter, the diagnosis can be quite difficult. Three major patterns of PRES were proposed by Bartynski, namely a holohemispheric watershed pattern, a superior frontal sulcus pattern

As more cases were described and more research was performed, a new hypothesis was proposed based upon the hypertension/hyperperfusion theory. This hypothesis stated that PRES was the result of acute and severe hypertension beyond the autoregulatory limits, leading to a breakthrough of the blood-brain barrier, hyperperfusion, capillary bed injury, fluid leakage and vasogenic edema (Bartynski, 2008b, Staykov and Schwab, 2011). Different animal studies supporting the hypertension/hyperperfusion theory and the success of immediate anti-hypertensive treatment in clinical setting strengthened the belief in this

However, several remarks have been posted questioning the reliability of this mechanism. For instance, hypertension is not or only mildly present in about 25% of patients with PRES, certainly not reaching the upper limits of autoregulation (Bartynski, 2008b, Staykov and Schwab, 2011). Secondly, solid evidence of hyperperfusion is scarce. Thirdly, the results from animal studies can not merely be extrapolated to humans. In patients with PRES, hypertension is induced by a 'systemic process/disease' while in animal studies hypertension is induced in healthy animals (Bartynski, 2008b and Staykov, 2011). At last, more advanced imaging techniques like cerebral angiography and MR angiography showed unexpectedly an inverse relation between the severity of hypertension and the extent of

In addition, as our knowledge of PRES expands, new insights in the pathophysiological mechanisms arise, pointing towards the older vasoconstriction-hypoperfusion theory. For example, all the well-known underlying pathologies (table 6) show activation of the cellular immune system, production of inflammatory cytokines and endothelial activation and injury, leading to a vasculopathy with vasoconstriction, hypoperfusion and subsequent ischemia as possible outcome (Bartynski, 2008b). It is clear that more investigations in this

The diagnosis of PRES is mainly based upon the combination of typical clinical symptoms

A laboratory work-out can give an indirect hint towards PRES by detecting thrombocytopenia, schistocytes and an increased serum lactate dehydrogenase (LDH) caused by endothelial injury which almost always accompanies PRES (Bartynski, 2008a;

Affected brain regions can be recognized by a hypodense signal on CT-scan but an MRI of the brain with fluid–attenuated inversion recovery (FLAIR) is the gold standard for the diagnosis of PRES because of its higher accuracy in detecting all affected areas (Casey et al., 2000). A pattern of symmetrical edema of the parietal-occipital regions is most frequently seen on neuro-imaging (Picture 1), but involvement of the frontal lobes, basal ganglia, brain stem and cerebellum have also been reported (Bartynski, 2008a; Hinchey et al., 1996;

Focal aberrations can be present along with the symmetrical edema but in absence of the latter, the diagnosis can be quite difficult. Three major patterns of PRES were proposed by Bartynski, namely a holohemispheric watershed pattern, a superior frontal sulcus pattern

more recent hypothesis.

**3.1.5 Diagnosis**

Staykov and Schwab, 2011).

Staykov and Schwab, 2011).

brain edema (Bartynski and Boardman, 2008).

area are needed to elucidate this complex subject.

and specific abnormalities on brain imaging.

and a dominant parietal-occipital pattern. These three typical patterns were seen in 99 of 136 patients with PRES. The other patients showed a partial or asymmetric variation of one of these major patterns (Bartynski and Boardman, 2007). Awareness of these different patterns is of great importance for a quick diagnosis and treatment, subsequently leading towards a better outcome.

Picture 1. An example of NMR imaging in PRES: hyperintense signal (white arrowheads) on T2-weighted (left) and FLAIR (right) images of symmetrical affected parieto-occipital regions.

MR diffusion weighted imaging (DWI) with calculation of the apparent diffusion coefficient (ADC) may have an additional value in distinguishing a vasogenic edema (in PRES) from a cytotoxic edema (infarction), especially given the differences in treatment strategies (Doelken, 2007).

Cerebral angiography (CA) and MR angiography (MRA) commonly show signs of diffuse or focal vasoconstriction (with sometimes a typical string-of-beads appearance) and vasculopathy (Bartynski and Boardman, 2008). MR perfusion mostly reveals a reduced blood flow in the affected areas (Bartynski, 2008a; Brubaker et al., 2005).

MR spectroscopy describes reduced N-acetylaspartate:choline and N-acetylaspartate: creatinine ratios suggesting neuronal, axonal or synaptic dysfunction (Bartynski, 2008a; Pavlakis, 1997; Staykov and Schwab, 2011). The presence of lactate in PRES accompanied by vasoconstriction is suggestive for ischemia (Bartynski, 2008a; Staykov and Schwab, 2011). It is clear that information and results obtained from the more recent and advanced imaging techniques like CA, MRA, MR perfusion and others are more in favor of the old vasoconstriction/hypoperfusion theory.

Neoplasm Related Encephalopathies 111

meningitis (Tan and Koralnik, 2010). JCV is even thought to play a role in different types of brain tumors, gastro-intestinal cancers and lung cancer, although its contribution to the

The brain lesions associated with PML are asymmetric and variable in size, subsequently leading to a variety of possible clinical symptoms. In contrast with PRES, PML is characterized by a subacute onset of symptoms, gradually progressing over weeks to

Signs of subcortical dementia with cognitive impairment are a common feature and often the first symptoms indicating the development of PML (Major, 2010). Motor dysfunctions often accompany the cognitive problems and can range from walking difficulties and deranged coordination to ataxia and hemiparesis (Major, 2010; Brew et al., 2010). Visual changes are also frequently reported with hemianopsia being the most prevalent one. Seizures have been described in about twenty percent of PML cases and can be expected if

Other possible symptoms are headaches, dysartria, aphasia and abulia (Lima et al., 2010).

As the disease progresses, the patient gradually develops global impairment eventually

Infection with the JC virus is imperative for the possible development of PML but the JC virus on its own is not enough to cause this neurological disorder. The presence of a

Until the 1980's, PML was a rare neuropathological disease mostly associated with hematological malignancies and systemic inflammatory disorders (Brew et al., 2010). With the outbreak of the AIDS pandemia in the mid-1980's, the incidence of PML rose spectacularly to a 50-fold increase. AIDS became the most important predisposing factor for developing PML, being present in about 3% of HIV-1 positive individuals (Major, 2010).

More recently, new case reports of PML arose from a rather unexpected corner, namely the treatment of patients with immunomodulatory drugs, with the monoclonal antibodies natalizumab, efalizumab and rituximab as best described entities. The first cases of PML were seen in 2005 in different phase III trials where patients received natalizumab for the treatment of multiple sclerosis (MS) or Chron's disease (Kleinschmidt-DeMasters and Tyler, 2005; Langer-Gould et al., 2005 and Van Assche et al., 2005 as cited in Berger et al., 2009 and Weissert, 2011). Diagnoses of PML in patients treated with efalizumab for psoriasis or with rituximab for lymphoproliferative disorders followed but to a lesser extent than

Each monoclonal antibody has its specific immunomodulatory characteristics (Berger et al., 2009) possibly providing the reason why some monoclonal antibodies are more frequently associated with PML than others. In addition, the disorder requiring immunomodulatory therapy can also be a predisposing condition for developing PML making it difficult to

predisposing immunocompromising condition is also an absolute necessity.

development of these cancers remains unraveled.

the lesions are in close contact with the cortex (Brew et al., 2010).

**3.2.2 Clinical manifestation**

leading to death if treatment fails.

**3.2.3 Etiology**

natalizumab.

months.

#### **3.1.6 Treatment**

Patients with PRES should be treated in a (neuro)critical care unit with close hemodynamic monitoring and the opportunity for intubation and ventilation in case of severe decrease in mental state. Cornerstone in the treatment of PRES is removing the causative pathology or drug. Specifically in cancer, the responsible chemotherapeutic agent(s) or targeted therapy should be reduced or even completely stopped when possible. About 75% of patients will present with a mild to severe elevated blood pressure which needs to be corrected with antihypertensive drugs. Nitroglycerine however should be avoided as it has been reported to aggravate the cerebral edema in PRES (Finsterer, 2003, as cited in Staykov and Schwab, 2011). In case of seizures or status epilepticus, benzodiazepines are given in the acute phase followed by long-term anti-convulsive therapy. Controversy remains about the duration of the anti-convulsive therapy. In some cases the treatment was successfully stopped after a few days, others continued the drugs for a couple of months. Seizures in pregnant women with eclampsia can be treated with magnesium sulfate.

#### **3.1.7 Prognosis**

As can be derived from the 'R' in the term PRES, this syndrome is usually completely reversible in a few days to weeks. A prompt diagnosis and correct treatment are therefore imperative. Sequellae however can arise, even with adequate treatment. Ischemia, parenchymal hemorrhage and epilepsy are possible complications of PRES with long-term consequences and a detrimental effect on quality of life (Staykov and Schwab, 2011).

Reoccurence of PRES has been reported anecdotally (Sweany et al., 2007). In cancer patients the question remains if the causative drug can safely be reintroduced after recovery from PRES. Many case reports describe a successful completion of the planned treatment scheme suggesting that the cancer treatment is an evoking but not sole causative factor in cancer treatment related PRES.

#### **3.2 Progressive multifocal leukoencephalopathy (PML)**

#### **3.2.1 Introduction**

Progressive multifocal leukoencephalopathy is a demyelinating disease of the white matter of the human brain. In 1958, Astrom et al. were the first to utter the term progressive multifocal leukoencephalopathy after their experience of similar clinical, neurological and pathological findings in two patients with chronic lymphocytic leukemia and one patient with Hodgkin's lymphoma (Astrom et al., 1958). At that time, the underlying cause of the disease was unknown. A few years later, electron microscopy of the brain lesions associated with PML revealed intranuclear particles in the oligodendrocytes which were later identified as virions derived from a papovavirus.

Eventually, more than ten years after the first description of PML, Padgett et al. were able to culture the virus out of a brain lesion in human fetal glial cells (Padgett et al., 1971). They named it the JC virus (JCV) according to the initials of the donor patient and it was later characterized as a human polyomavirus.

More recently, next to PML, other neurological disorders have been associated with JCV, namely JC virus granule cell neuronopathy, JC virus encephalopathy and JC virus

Patients with PRES should be treated in a (neuro)critical care unit with close hemodynamic monitoring and the opportunity for intubation and ventilation in case of severe decrease in mental state. Cornerstone in the treatment of PRES is removing the causative pathology or drug. Specifically in cancer, the responsible chemotherapeutic agent(s) or targeted therapy should be reduced or even completely stopped when possible. About 75% of patients will present with a mild to severe elevated blood pressure which needs to be corrected with antihypertensive drugs. Nitroglycerine however should be avoided as it has been reported to aggravate the cerebral edema in PRES (Finsterer, 2003, as cited in Staykov and Schwab, 2011). In case of seizures or status epilepticus, benzodiazepines are given in the acute phase followed by long-term anti-convulsive therapy. Controversy remains about the duration of the anti-convulsive therapy. In some cases the treatment was successfully stopped after a few days, others continued the drugs for a couple of months. Seizures in pregnant women

As can be derived from the 'R' in the term PRES, this syndrome is usually completely reversible in a few days to weeks. A prompt diagnosis and correct treatment are therefore imperative. Sequellae however can arise, even with adequate treatment. Ischemia, parenchymal hemorrhage and epilepsy are possible complications of PRES with long-term

Reoccurence of PRES has been reported anecdotally (Sweany et al., 2007). In cancer patients the question remains if the causative drug can safely be reintroduced after recovery from PRES. Many case reports describe a successful completion of the planned treatment scheme suggesting that the cancer treatment is an evoking but not sole causative factor in cancer

Progressive multifocal leukoencephalopathy is a demyelinating disease of the white matter of the human brain. In 1958, Astrom et al. were the first to utter the term progressive multifocal leukoencephalopathy after their experience of similar clinical, neurological and pathological findings in two patients with chronic lymphocytic leukemia and one patient with Hodgkin's lymphoma (Astrom et al., 1958). At that time, the underlying cause of the disease was unknown. A few years later, electron microscopy of the brain lesions associated with PML revealed intranuclear particles in the oligodendrocytes which were later

Eventually, more than ten years after the first description of PML, Padgett et al. were able to culture the virus out of a brain lesion in human fetal glial cells (Padgett et al., 1971). They named it the JC virus (JCV) according to the initials of the donor patient and it was later

More recently, next to PML, other neurological disorders have been associated with JCV, namely JC virus granule cell neuronopathy, JC virus encephalopathy and JC virus

consequences and a detrimental effect on quality of life (Staykov and Schwab, 2011).

with eclampsia can be treated with magnesium sulfate.

**3.2 Progressive multifocal leukoencephalopathy (PML)**

identified as virions derived from a papovavirus.

characterized as a human polyomavirus.

**3.1.6 Treatment**

**3.1.7 Prognosis**

treatment related PRES.

**3.2.1 Introduction**

meningitis (Tan and Koralnik, 2010). JCV is even thought to play a role in different types of brain tumors, gastro-intestinal cancers and lung cancer, although its contribution to the development of these cancers remains unraveled.

#### **3.2.2 Clinical manifestation**

The brain lesions associated with PML are asymmetric and variable in size, subsequently leading to a variety of possible clinical symptoms. In contrast with PRES, PML is characterized by a subacute onset of symptoms, gradually progressing over weeks to months.

Signs of subcortical dementia with cognitive impairment are a common feature and often the first symptoms indicating the development of PML (Major, 2010). Motor dysfunctions often accompany the cognitive problems and can range from walking difficulties and deranged coordination to ataxia and hemiparesis (Major, 2010; Brew et al., 2010). Visual changes are also frequently reported with hemianopsia being the most prevalent one. Seizures have been described in about twenty percent of PML cases and can be expected if the lesions are in close contact with the cortex (Brew et al., 2010).

Other possible symptoms are headaches, dysartria, aphasia and abulia (Lima et al., 2010).

As the disease progresses, the patient gradually develops global impairment eventually leading to death if treatment fails.

#### **3.2.3 Etiology**

Infection with the JC virus is imperative for the possible development of PML but the JC virus on its own is not enough to cause this neurological disorder. The presence of a predisposing immunocompromising condition is also an absolute necessity.

Until the 1980's, PML was a rare neuropathological disease mostly associated with hematological malignancies and systemic inflammatory disorders (Brew et al., 2010). With the outbreak of the AIDS pandemia in the mid-1980's, the incidence of PML rose spectacularly to a 50-fold increase. AIDS became the most important predisposing factor for developing PML, being present in about 3% of HIV-1 positive individuals (Major, 2010).

More recently, new case reports of PML arose from a rather unexpected corner, namely the treatment of patients with immunomodulatory drugs, with the monoclonal antibodies natalizumab, efalizumab and rituximab as best described entities. The first cases of PML were seen in 2005 in different phase III trials where patients received natalizumab for the treatment of multiple sclerosis (MS) or Chron's disease (Kleinschmidt-DeMasters and Tyler, 2005; Langer-Gould et al., 2005 and Van Assche et al., 2005 as cited in Berger et al., 2009 and Weissert, 2011). Diagnoses of PML in patients treated with efalizumab for psoriasis or with rituximab for lymphoproliferative disorders followed but to a lesser extent than natalizumab.

Each monoclonal antibody has its specific immunomodulatory characteristics (Berger et al., 2009) possibly providing the reason why some monoclonal antibodies are more frequently associated with PML than others. In addition, the disorder requiring immunomodulatory therapy can also be a predisposing condition for developing PML making it difficult to

Neoplasm Related Encephalopathies 113

given the rarity of PML and the unlikeliness of establishing a long-term latency without

The most popular theory is reactivation of JCV in peripheral blood mononuclear cells causing hematogenous dissemination of the virus across the body with B-lymphocytes having the ability to cross the blood-brain barrier (Berger et al., 2009; Brew et al, 2010; White

An alternative model was proposed by White and Khalili where extracellular cytokines cause a reactivation of latent JCV in the brain (White and Khalili, 2011). In both models, reactivation and active replication of JCV is only possible in light of a reduction in

Regardless of the 2 different models, eventually, activated neurotropic JC virus is present in the brain and has the capability of infecting oligodendrocytes and astrocytes, leading to cell lysis and further spreading of the virus to adjacent cells. Lysis of oligodendrocytes causes demyelination, a process responsible for the typical clinical and neuroradiological features

Initial JCV infection, mainly in childhood or adulthood, through inhalation

(brain as functional site of latent infection remains controversial)

(tonsils) or ingestion of contaminated food or water (gastro-intestinal system)

Establishment of latent infection in kidneys, bone marrow and lymphoid tissues

Rearrangement in the non-coding control region of JCV (within B-cells) leading to

Reactivation of JCV in PBMCs with hematogenous dissemination through the

The diagnosis of PML is based on typical clinical manifestations, specific neuroradiological

whole body and crossing the blood-brain barrier via B-cells

inflammatory consequences during viral clearance (Major, 2010).

immunosurveillance (as described in partim etiology).

**Proposed stages of PML development**

a neurotropic JCV strain

Failed immunosurveillance in the periphery

 Failed immunosurveillance in the brain Table 7. Proposed stages of PML development

 Entry of neurotropic JCV into the brain (via B-cells) Establishment of productive infection of oligodendrocytes

findings and detection of JCV-DNA in the cerebrospinal fluid (CSF).

Reactivation of JCV:

and Khalili, 2011).

Invasion of the brain:

Primary infection

Latent infection

Reactivation

Brain infection

**3.2.5 Diagnosis**

of PML.

assess the real influence of the therapy on the incidence of PML. For example, rituximab is used for the treatment of lymphoproliferative disorders and both are linked with PML.

Next to monoclonal antibodies, several anti-neoplastic and immunosuppressive therapies like methotrexate, cyclophosphamide, carboplatinum/gemcitabine, fludarabine and mycophenolate mofetil have been reported as causative agents for PML (Brew et al., 2010; Palmieri et al., 2010).

#### **3.2.4 Pathophysiology**

The pathophysiological mechanism behind PML is complicated and until now not fully elucidated. However, to some degree there is a consensus about the major steps that need to be fulfilled for the development of PML (table 7). These steps include: primary infection with JCV, period of latent infection, reactivation of JCV and eventually invasion into the brain (Brew et al., 2010; Major, 2010; White and Khalili, 2011).

Primary infection:

A primary infection with the JC virus is indispensable for the possible development of PML. Primary infection occurs mainly in the childhood but continues into middle age. JCV is a hemagglutinating virus and hemagglutination inhibition assays were able to detect JCV antibodies in 50-90% of adults (Taguchi et al., 1982 and Walker and Padgett, 1983 as cited in White and Khalili, 2011). The route of transmission is believed to be inhalation of the virus with infection of the tonsils or ingestion of contaminated water or food and uptake of the virus by the gastro-intestinal tract. A primary infection usually occurs without symptoms while some organs stay behind with latent infection.

Period of latency:

Based upon detection of JCV in urine and the presence of JCV DNA in tissue of PML and non-PML patients, at least 3 organs are believed to harbor latent infection: the kidney, the bone marrow and lymphoid tissues like the tonsils, spleen, B-lymphocytes and CD 34+ hematopoetic cells (Major, 2010; White and Khalili, 2011).

Molecular and genetic characterization of JCV found in these tissues and cells led to the discovery of two different types, namely archetype JCV and prototype JCV. The difference between these two types is the appearance of rearrangements in the non-coding control region (NCCR) of the virus leading to a neurotropic prototype JCV (Berger et al., 2009).

Based upon these findings, following hypothesis was put forward: archetypal JCV is responsible for the primary infection, possesses a normal NCCR and is not able to infect human glial cells. During latency, rearrangements in the NCCR occur leading to the more aggressive, neurotropic prototype JCV. This hypothesis was supported by the intriguing observation of possible latency in B-cells, possessing all the necessary machinery for gene rearrangement (Berger et al, 2009). Moreover, the fact that PML remains a rare entity despite the high prevalence of JCV-infection points towards the necessity of this genetic alteration.

Of note, controversy remains regarding the brain as possible site of latency. Although prototype JCV-DNA has been found in normal non-PML brain tissue (White and Khalili, 2011), some investigators question the possibility of the brain as a functional latency site given the rarity of PML and the unlikeliness of establishing a long-term latency without inflammatory consequences during viral clearance (Major, 2010).

#### Reactivation of JCV:

112 Miscellanea on Encephalopathies – A Second Look

assess the real influence of the therapy on the incidence of PML. For example, rituximab is used for the treatment of lymphoproliferative disorders and both are linked with PML.

Next to monoclonal antibodies, several anti-neoplastic and immunosuppressive therapies like methotrexate, cyclophosphamide, carboplatinum/gemcitabine, fludarabine and mycophenolate mofetil have been reported as causative agents for PML (Brew et al., 2010;

The pathophysiological mechanism behind PML is complicated and until now not fully elucidated. However, to some degree there is a consensus about the major steps that need to be fulfilled for the development of PML (table 7). These steps include: primary infection with JCV, period of latent infection, reactivation of JCV and eventually invasion into the

A primary infection with the JC virus is indispensable for the possible development of PML. Primary infection occurs mainly in the childhood but continues into middle age. JCV is a hemagglutinating virus and hemagglutination inhibition assays were able to detect JCV antibodies in 50-90% of adults (Taguchi et al., 1982 and Walker and Padgett, 1983 as cited in White and Khalili, 2011). The route of transmission is believed to be inhalation of the virus with infection of the tonsils or ingestion of contaminated water or food and uptake of the virus by the gastro-intestinal tract. A primary infection usually occurs without symptoms

Based upon detection of JCV in urine and the presence of JCV DNA in tissue of PML and non-PML patients, at least 3 organs are believed to harbor latent infection: the kidney, the bone marrow and lymphoid tissues like the tonsils, spleen, B-lymphocytes and CD 34+

Molecular and genetic characterization of JCV found in these tissues and cells led to the discovery of two different types, namely archetype JCV and prototype JCV. The difference between these two types is the appearance of rearrangements in the non-coding control region (NCCR) of the virus leading to a neurotropic prototype JCV (Berger et al., 2009).

Based upon these findings, following hypothesis was put forward: archetypal JCV is responsible for the primary infection, possesses a normal NCCR and is not able to infect human glial cells. During latency, rearrangements in the NCCR occur leading to the more aggressive, neurotropic prototype JCV. This hypothesis was supported by the intriguing observation of possible latency in B-cells, possessing all the necessary machinery for gene rearrangement (Berger et al, 2009). Moreover, the fact that PML remains a rare entity despite the high prevalence of JCV-infection points towards the necessity of this genetic alteration. Of note, controversy remains regarding the brain as possible site of latency.

Palmieri et al., 2010).

Primary infection:

Period of latency:

**3.2.4 Pathophysiology**

The most popular theory is reactivation of JCV in peripheral blood mononuclear cells causing hematogenous dissemination of the virus across the body with B-lymphocytes having the ability to cross the blood-brain barrier (Berger et al., 2009; Brew et al, 2010; White and Khalili, 2011).

An alternative model was proposed by White and Khalili where extracellular cytokines cause a reactivation of latent JCV in the brain (White and Khalili, 2011). In both models, reactivation and active replication of JCV is only possible in light of a reduction in immunosurveillance (as described in partim etiology).

Invasion of the brain:

Regardless of the 2 different models, eventually, activated neurotropic JC virus is present in the brain and has the capability of infecting oligodendrocytes and astrocytes, leading to cell lysis and further spreading of the virus to adjacent cells. Lysis of oligodendrocytes causes demyelination, a process responsible for the typical clinical and neuroradiological features of PML.

#### **Proposed stages of PML development**

Primary infection

 Initial JCV infection, mainly in childhood or adulthood, through inhalation (tonsils) or ingestion of contaminated food or water (gastro-intestinal system)

Latent infection

 Establishment of latent infection in kidneys, bone marrow and lymphoid tissues (brain as functional site of latent infection remains controversial) Rearrangement in the non-coding control region of JCV (within B-cells) leading to a neurotropic JCV strain

#### Reactivation

 Failed immunosurveillance in the periphery Reactivation of JCV in PBMCs with hematogenous dissemination through the whole body and crossing the blood-brain barrier via B-cells

#### Brain infection

 Entry of neurotropic JCV into the brain (via B-cells) Establishment of productive infection of oligodendrocytes Failed immunosurveillance in the brain

Table 7. Proposed stages of PML development

#### **3.2.5 Diagnosis**

The diagnosis of PML is based on typical clinical manifestations, specific neuroradiological findings and detection of JCV-DNA in the cerebrospinal fluid (CSF).

Neoplasm Related Encephalopathies 115

MR spectroscopy in PML may reveal a diminished N-acetylaspartate linked with neuronal loss and dysfunction, increased choline indicating demyelination, high lactate and lipid levels correlated with necrosis, and a temporary increase of myoinositol in evolving lesions (Brew et al., 2010 and Shah et al., 2010). None of these findings, however, are specific for

Detection of JCV-DNA in CSF by PCR amplification is imperative for diagnosing PML. However, negative results do not simply exclude PML as JCV-DNA can still be undetectable in the beginning of the disease course. Moreover, the quality of JCV-DNA testing can variate substantially between different testing facilities. In case of a negative result and strong clinical and imaging evidence, a repeat lumbar puncture is recommended. If JCV-DNA remains undetected in the CSF, a stereotatic brain biopsy can be helpful. Although this is a highly invasive technique, it may often provide the necessary information for a correct

Histopathological features of PML are areas of demyelination. These lesions contain a moderate number of foamy astrocytes and only scant perivascular lymphocytes. Lymphocytic infiltration may be more common in HIV-positive PML and may be associated with a slightly better prognosis. A striking feature, particularly in older lesions, is the presence of very large astrocytes with bizarre, pleiomorphic nuclei. Viral inclusions are seen in the periphery of the foci of demyelination and are localized in the enlarged nuclei of oligodendrocytes (Brew et al., 2010; Ellison et al., 2004). JCV-DNA can be detected by in situ hybridization. Immunohistochemistry is often used to confirm diagnosis by revealing the

Picture 3. Hematoxylin-eosin stain (left) in a case of PML (magnification 200x) reveals foci of demyelination with macrophages and scattered glial cells showing hyperchromatic and atypical nuclei (arrows), sometimes with ground glass appearance. The diagnosis of PML is

Although different agents with antiviral activity have been tried, there is no adequate

Cytarabine was able to inhibit JCV replication in vitro but failed to show improvement of survival in randomized controlled trials (Hall et al., 1998 as cited in Brew et al., 2010).

confirmed by immunostain for JC virus (right) in the affected nuclei (arrows).

PML and therefore can not be used for definitive diagnostic purposes.

presence of JCV antigen (Picture 3) (Brew et al., 2010; Major et al., 1992).

diagnosis.

**3.2.6 Treatment**

treatment for PML as we speak.

 MRI of the brain has proven its superiority to CT scanning in documenting the number and extent of the lesions (Post MJ et al., 1986 as cited in Major et al., 1992) and in detecting the lesions in the initial stages of the disease (Shah et al., 2010).

PML mainly presents itself on MRI as single or asymmetric multifocal white matter lesions, enlarging and becoming confluent as the disease progresses. The lesions are typically hypointense on T1- and hyperintense on T2-weighted and FLAIR images compared to the normal white matter (Picture 2) (Shah et al., 2010). There usually is no mass effect, no edema and no gadolinium enhancement. However, gadolinium enhancement is frequently seen in natalizumab treated patients as documented in 43% of cases (Calabrese et al., 2007 and Clifford et al., 2010 as cited in Brew et al., 2010). Involvement of the parieto-occipital white matter, corpus callosum and posterior fossa is commonly seen while lesions restricted to the cerebellum, brainstem or pyramidal tract are also possible. Involvement of the spinal cord is rare, certainly in the beginning of PML, and when present alternative causes should be considered first. Although PML is known for its white matter lesions, involvement of the grey matter has been detected in up to 50% of patients with PML (Mark AS and Atlas SW, 1989 as cited in Shah et al., 2010).

Picture 2. An example of NMR imaging in PML: hyperintens signal on T2-weighted (left) and FLAIR (right) images indicating asymmetric white matter lesions.

DWI MRI with ADC mapping provides additional information for characterizing the detected aberrations on MRI. A high signal on DWI with a low ADC value indicates regions with active infection as seen in new lesions and at the border of larger lesions while the center of these larger lesions usually have elevated ADC values (Brew et al., 2010 and Shah et al., 2010).

 MRI of the brain has proven its superiority to CT scanning in documenting the number and extent of the lesions (Post MJ et al., 1986 as cited in Major et al., 1992) and in detecting the lesions in the initial stages of the disease (Shah et

PML mainly presents itself on MRI as single or asymmetric multifocal white matter lesions, enlarging and becoming confluent as the disease progresses. The lesions are typically hypointense on T1- and hyperintense on T2-weighted and FLAIR images compared to the normal white matter (Picture 2) (Shah et al., 2010). There usually is no mass effect, no edema and no gadolinium enhancement. However, gadolinium enhancement is frequently seen in natalizumab treated patients as documented in 43% of cases (Calabrese et al., 2007 and Clifford et al., 2010 as cited in Brew et al., 2010). Involvement of the parieto-occipital white matter, corpus callosum and posterior fossa is commonly seen while lesions restricted to the cerebellum, brainstem or pyramidal tract are also possible. Involvement of the spinal cord is rare, certainly in the beginning of PML, and when present alternative causes should be considered first. Although PML is known for its white matter lesions, involvement of the grey matter has been detected in up to 50% of patients with PML (Mark AS and Atlas SW,

Picture 2. An example of NMR imaging in PML: hyperintens signal on T2-weighted (left)

DWI MRI with ADC mapping provides additional information for characterizing the detected aberrations on MRI. A high signal on DWI with a low ADC value indicates regions with active infection as seen in new lesions and at the border of larger lesions while the center of these larger lesions usually have elevated ADC values (Brew et al., 2010 and Shah

and FLAIR (right) images indicating asymmetric white matter lesions.

al., 2010).

et al., 2010).

1989 as cited in Shah et al., 2010).

MR spectroscopy in PML may reveal a diminished N-acetylaspartate linked with neuronal loss and dysfunction, increased choline indicating demyelination, high lactate and lipid levels correlated with necrosis, and a temporary increase of myoinositol in evolving lesions (Brew et al., 2010 and Shah et al., 2010). None of these findings, however, are specific for PML and therefore can not be used for definitive diagnostic purposes.

Detection of JCV-DNA in CSF by PCR amplification is imperative for diagnosing PML. However, negative results do not simply exclude PML as JCV-DNA can still be undetectable in the beginning of the disease course. Moreover, the quality of JCV-DNA testing can variate substantially between different testing facilities. In case of a negative result and strong clinical and imaging evidence, a repeat lumbar puncture is recommended. If JCV-DNA remains undetected in the CSF, a stereotatic brain biopsy can be helpful. Although this is a highly invasive technique, it may often provide the necessary information for a correct diagnosis.

Histopathological features of PML are areas of demyelination. These lesions contain a moderate number of foamy astrocytes and only scant perivascular lymphocytes. Lymphocytic infiltration may be more common in HIV-positive PML and may be associated with a slightly better prognosis. A striking feature, particularly in older lesions, is the presence of very large astrocytes with bizarre, pleiomorphic nuclei. Viral inclusions are seen in the periphery of the foci of demyelination and are localized in the enlarged nuclei of oligodendrocytes (Brew et al., 2010; Ellison et al., 2004). JCV-DNA can be detected by in situ hybridization. Immunohistochemistry is often used to confirm diagnosis by revealing the presence of JCV antigen (Picture 3) (Brew et al., 2010; Major et al., 1992).

Picture 3. Hematoxylin-eosin stain (left) in a case of PML (magnification 200x) reveals foci of demyelination with macrophages and scattered glial cells showing hyperchromatic and atypical nuclei (arrows), sometimes with ground glass appearance. The diagnosis of PML is confirmed by immunostain for JC virus (right) in the affected nuclei (arrows).

#### **3.2.6 Treatment**

Although different agents with antiviral activity have been tried, there is no adequate treatment for PML as we speak.

Cytarabine was able to inhibit JCV replication in vitro but failed to show improvement of survival in randomized controlled trials (Hall et al., 1998 as cited in Brew et al., 2010).

Neoplasm Related Encephalopathies 117

inflammatory syndrome or IRIS, marked by a transient worsening of the neurological symptoms and contrast enhancement of the PML lesions on brain imaging. In severe cases of IRIS, edema with mass effect and brain herniation may occur with possible fatal

This might give IRIS a negative accent while in fact, development of IRIS in PML does not negatively influence PML survival and may even be potentially linked with prolonged survival and possible cure given the fact that IRIS actually reflects a (too) fast recovery of the

Successful treatment of IRIS has been reported with high dose steroids to suppress the inflammation, although this remains controversial since these are also immunosuppressants with possible detrimental effects on the underlying immunocompromising diseases

Encephalopathy is a clinical syndrome, seen in many patients with underlying systemic diseases. In this chapter, we focused on uncommon clinical pictures presenting as an

As mentioned above, paraneoplastic neurological syndromes precede a diagnosis of malignancy in 60% of all cases, emphasizing that recognition of this syndrome may lead to early detection of an associated malignancy, with subsequent advantages in therapy

Initially an auto-immune mediated pathophysiological mechanism was assumed, but the mechanisms of most paraneoplastic neurological syndromes could not be elucidated up till now. We hope that further research in this intriguing immune-neuro-oncological field will help understand the mechanisms of cancer and PNS and that manipulating the immune

Although PRES and PML are rare diseases, recognizing these clinical entities can be of vital importance. Their prompt diagnosis and correct management not only positively influences the clinical outcome and survival but also reduces a possible decrease in the patients' quality of life which is already greatly impaired due to the seriousness of their underlying diseases. For both PRES and PML, predictive markers and a better understanding of the pathophysiological mechanisms could be useful in terms of prevention and more adequate

With the fast changing world of cancer therapies, especially the targeted therapies, more reports of PRES and PML are expected but also new encephalopathies can arise. It is our responsibility to closely monitor patients during and after cancer treatment and to be

The authors would like to thank Dr. Caroline Van Den Broecke for kindly providing the

immune system (Tan and Koralnik, 2011; Weissert, 2011).

encephalopathy and discussed the causing pathophysiology.

system can lead to tumour treatment and regression.

vigilant for unexpected adverse events.

anatomopathological images of PML.

**5. Acknowledgements**

treatment. Further research comprising these topics is ongoing.

responsible for inducing PML in the first place (Tan and Koralnik, 2011).

outcome.

**4. Conclusion**

response and prognosis.

Cidofovir, an antiviral agent against cytomegalovirus infection, was tested in different trials with HIV-positive PML patients and showed contradictory results in terms of survival or PML-related residual disability (Tan and Koralnik, 2011).

The discovery that JCV binds the 5-HT2A receptor before infecting the cell led to the use of mirtazapine (a serotonin receptor blocker) as possible treatment for PML. However, the positive results from case reports have not been consolidated by large studies (Brew et al, 2010; Tan and Koralnik, 2011).

More recently, promising in vitro data were reported using the anti-malaria drug mefloquine. This led to the set up of a momentarily ongoing large clinical trial evaluating the use of mefloquine in the treatment of PML (clinicaltrials.gov, 2009).

With the lack of an effective antiviral agent the treatment of PML is mainly focused on improvement of the impaired immune status of the host. For cancer patients, this usually means reducing or even stopping the immunosuppressive agents allowing the immune system to recover with, hopefully, subsequent containment of the JCV infection.

In case of immunomodulatory monoclonal antibody associated PML, some specific characteristics should be considered. For example, natalizumab has a half-life of 11 days in the blood and even after immediate cessation of the drug, it still has biological activity for 3 months during which PML can further progress (Tan and Koralnik, 2011). Plasma exchange for quick removal of serum natalizumab has been tried but exposes the patient to a high risk of developing immune reconstitution inflammatory syndrome (IRIS) with possible fatal outcome (described in partim prognosis). Rituximab on the other hand, induces a long-term decrease in B-cells and has already cleared the circulation long before PML occurs. Thus, immediate cessation of the drug or plasma exchange are of no use in this situation.

Better understanding of the specific role of the different monoclonal antibodies in JCV reactivation and more knowledge regarding the development of IRIS during immune reconstitution will be necessary for a better management of immunomodulatory monoclonal antibody associated PML (Tan and Koralnik, 2011).

#### **3.2.7 Prognosis**

PML is a deleterious disease with mortality rates up to 90% within a few months when left untreated. However, if the immune response can be restored, survival significantly improves. A clinical neurologic recovery, contrast enhancement of PML lesions on neuroimaging, high CD4+ T-lymphocyte count at disease onset and the appearance of JCVspecific CD8+ cytotoxic T-lymphocytes in the blood within three months of the diagnosis are considered positive prognostic factors (Berger et al., 1998; Marzocchetti et al., 2009). A high JCV-DNA load in CSF is considered a determinant of poor survival.

The outcome in long-term survivors of PML can range from complete recovery to sustained severe neurologic disabilities requiring institutionalization (Lima et al., 2010). Patients with small PML-lesions and a short symptom-to-diagnosis time appear to have a better outcome while involvement of the cerebellum or brainstem may indicate a worse prognosis (Brew et al., 2010; Lima et al., 2010; Vermersch et al., 2011).

Although reconstitution of the immune system is a key factor for a better survival in PML, it can be accompanied by an acute inflammatory reaction called immune reconstitution

Cidofovir, an antiviral agent against cytomegalovirus infection, was tested in different trials with HIV-positive PML patients and showed contradictory results in terms of survival or

The discovery that JCV binds the 5-HT2A receptor before infecting the cell led to the use of mirtazapine (a serotonin receptor blocker) as possible treatment for PML. However, the positive results from case reports have not been consolidated by large studies (Brew et al,

More recently, promising in vitro data were reported using the anti-malaria drug mefloquine. This led to the set up of a momentarily ongoing large clinical trial evaluating

With the lack of an effective antiviral agent the treatment of PML is mainly focused on improvement of the impaired immune status of the host. For cancer patients, this usually means reducing or even stopping the immunosuppressive agents allowing the immune

In case of immunomodulatory monoclonal antibody associated PML, some specific characteristics should be considered. For example, natalizumab has a half-life of 11 days in the blood and even after immediate cessation of the drug, it still has biological activity for 3 months during which PML can further progress (Tan and Koralnik, 2011). Plasma exchange for quick removal of serum natalizumab has been tried but exposes the patient to a high risk of developing immune reconstitution inflammatory syndrome (IRIS) with possible fatal outcome (described in partim prognosis). Rituximab on the other hand, induces a long-term decrease in B-cells and has already cleared the circulation long before PML occurs. Thus,

Better understanding of the specific role of the different monoclonal antibodies in JCV reactivation and more knowledge regarding the development of IRIS during immune reconstitution will be necessary for a better management of immunomodulatory monoclonal

PML is a deleterious disease with mortality rates up to 90% within a few months when left untreated. However, if the immune response can be restored, survival significantly improves. A clinical neurologic recovery, contrast enhancement of PML lesions on neuroimaging, high CD4+ T-lymphocyte count at disease onset and the appearance of JCVspecific CD8+ cytotoxic T-lymphocytes in the blood within three months of the diagnosis are considered positive prognostic factors (Berger et al., 1998; Marzocchetti et al., 2009). A

The outcome in long-term survivors of PML can range from complete recovery to sustained severe neurologic disabilities requiring institutionalization (Lima et al., 2010). Patients with small PML-lesions and a short symptom-to-diagnosis time appear to have a better outcome while involvement of the cerebellum or brainstem may indicate a worse prognosis (Brew et

Although reconstitution of the immune system is a key factor for a better survival in PML, it can be accompanied by an acute inflammatory reaction called immune reconstitution

PML-related residual disability (Tan and Koralnik, 2011).

antibody associated PML (Tan and Koralnik, 2011).

al., 2010; Lima et al., 2010; Vermersch et al., 2011).

**3.2.7 Prognosis**

the use of mefloquine in the treatment of PML (clinicaltrials.gov, 2009).

system to recover with, hopefully, subsequent containment of the JCV infection.

immediate cessation of the drug or plasma exchange are of no use in this situation.

high JCV-DNA load in CSF is considered a determinant of poor survival.

2010; Tan and Koralnik, 2011).

inflammatory syndrome or IRIS, marked by a transient worsening of the neurological symptoms and contrast enhancement of the PML lesions on brain imaging. In severe cases of IRIS, edema with mass effect and brain herniation may occur with possible fatal outcome.

This might give IRIS a negative accent while in fact, development of IRIS in PML does not negatively influence PML survival and may even be potentially linked with prolonged survival and possible cure given the fact that IRIS actually reflects a (too) fast recovery of the immune system (Tan and Koralnik, 2011; Weissert, 2011).

Successful treatment of IRIS has been reported with high dose steroids to suppress the inflammation, although this remains controversial since these are also immunosuppressants with possible detrimental effects on the underlying immunocompromising diseases responsible for inducing PML in the first place (Tan and Koralnik, 2011).

#### **4. Conclusion**

Encephalopathy is a clinical syndrome, seen in many patients with underlying systemic diseases. In this chapter, we focused on uncommon clinical pictures presenting as an encephalopathy and discussed the causing pathophysiology.

As mentioned above, paraneoplastic neurological syndromes precede a diagnosis of malignancy in 60% of all cases, emphasizing that recognition of this syndrome may lead to early detection of an associated malignancy, with subsequent advantages in therapy response and prognosis.

Initially an auto-immune mediated pathophysiological mechanism was assumed, but the mechanisms of most paraneoplastic neurological syndromes could not be elucidated up till now. We hope that further research in this intriguing immune-neuro-oncological field will help understand the mechanisms of cancer and PNS and that manipulating the immune system can lead to tumour treatment and regression.

Although PRES and PML are rare diseases, recognizing these clinical entities can be of vital importance. Their prompt diagnosis and correct management not only positively influences the clinical outcome and survival but also reduces a possible decrease in the patients' quality of life which is already greatly impaired due to the seriousness of their underlying diseases. For both PRES and PML, predictive markers and a better understanding of the pathophysiological mechanisms could be useful in terms of prevention and more adequate treatment. Further research comprising these topics is ongoing.

With the fast changing world of cancer therapies, especially the targeted therapies, more reports of PRES and PML are expected but also new encephalopathies can arise. It is our responsibility to closely monitor patients during and after cancer treatment and to be vigilant for unexpected adverse events.

#### **5. Acknowledgements**

The authors would like to thank Dr. Caroline Van Den Broecke for kindly providing the anatomopathological images of PML.

Neoplasm Related Encephalopathies 119

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**6**

 *Birmingham, AL*

*USA*

**Hepatic Encephalopathy**

*Division of Gastroenterology and Hepatology*

Jeffrey E. Juneau and Brendan M. McGuire

*University of Alabama at Birmingham, Department of Medicine,*

Hepatic encephalopathy (HE) is a neuropsychiatric condition affecting patients with cirrhosis, acute liver failure and portal-systemic bypass1, 2, 3. The neuropsychiatric abnormalities include changes in levels of consciousness, behavior, intellect, and neurologic exam. The changes in levels of consciousness can range from altered sleep habits to coma. HE is a frequent complication in patients with cirrhosis and is broadly classified as minimal HE and overt HE. Minimal HE is defined as subclinical cognitive dysfunction, only detected by neuropsychiatric testing, and is present in up to 80% of patients with cirrhosis4. Overt HE is defined in patients with active HE or a previous episode of HE and is present in 30-45% of

HE results from the overproduction or impaired metabolism of one or more neurotoxin. The general consensus is that ammonia with inflammation in the serum is believed to be the underlying trigger to developing HE. Normally, ammonia enters the portal system from the gut. When the liver is unable to clear ammonia, secondary to a limited number of viable hepatocytes or portal-systemic shunting, ammonia can enter the systemic circulation and enter brain tissue. Elevated ammonia with inflammation can impair normal neurotransmission and result in a variety of neuropsychiatric abnormalities6. The

The most common classification used for research purposes is the West Haven Criteria (also called Conn Score) (table I-1)8. The West Haven Criteria is graded with a range of 0-4. The far ends of the spectrum, grades 0 and 4, have fairly obvious clinical manifestations with no abnormalities and comatose, respectively 8, 9. However, the major criticism of the West Haven Criteria is deciphering the middle categories, 1-3, which can be difficult to reproduce

The World Congress of Gastroenterology developed a classification system for HE in 1998 based on underlying hepatic abnormalities. The three types are **A, B,** and **C** and are associated with **A**cute liver failure, portal systemic **B**ypass without intrinsic liver disease, and **C**irrhosis, respectively 2, 3, 10. Type C can be subcategorized into persistent, episodic, and

inflammatory component is usually related to bleeding, dehydration or sepsis4.

due to the subjectivity involved with the assessment.

**1. Introduction**

patients with cirrhosis5.

**1.1 Classification**

### **6**

### **Hepatic Encephalopathy**

Jeffrey E. Juneau and Brendan M. McGuire

*University of Alabama at Birmingham, Department of Medicine, Division of Gastroenterology and Hepatology Birmingham, AL USA*

#### **1. Introduction**

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305

Hepatic encephalopathy (HE) is a neuropsychiatric condition affecting patients with cirrhosis, acute liver failure and portal-systemic bypass1, 2, 3. The neuropsychiatric abnormalities include changes in levels of consciousness, behavior, intellect, and neurologic exam. The changes in levels of consciousness can range from altered sleep habits to coma. HE is a frequent complication in patients with cirrhosis and is broadly classified as minimal HE and overt HE. Minimal HE is defined as subclinical cognitive dysfunction, only detected by neuropsychiatric testing, and is present in up to 80% of patients with cirrhosis4. Overt HE is defined in patients with active HE or a previous episode of HE and is present in 30-45% of patients with cirrhosis5.

HE results from the overproduction or impaired metabolism of one or more neurotoxin. The general consensus is that ammonia with inflammation in the serum is believed to be the underlying trigger to developing HE. Normally, ammonia enters the portal system from the gut. When the liver is unable to clear ammonia, secondary to a limited number of viable hepatocytes or portal-systemic shunting, ammonia can enter the systemic circulation and enter brain tissue. Elevated ammonia with inflammation can impair normal neurotransmission and result in a variety of neuropsychiatric abnormalities6. The inflammatory component is usually related to bleeding, dehydration or sepsis4.

#### **1.1 Classification**

The most common classification used for research purposes is the West Haven Criteria (also called Conn Score) (table I-1)8. The West Haven Criteria is graded with a range of 0-4. The far ends of the spectrum, grades 0 and 4, have fairly obvious clinical manifestations with no abnormalities and comatose, respectively 8, 9. However, the major criticism of the West Haven Criteria is deciphering the middle categories, 1-3, which can be difficult to reproduce due to the subjectivity involved with the assessment.

The World Congress of Gastroenterology developed a classification system for HE in 1998 based on underlying hepatic abnormalities. The three types are **A, B,** and **C** and are associated with **A**cute liver failure, portal systemic **B**ypass without intrinsic liver disease, and **C**irrhosis, respectively 2, 3, 10. Type C can be subcategorized into persistent, episodic, and

Hepatic Encephalopathy 123

Due to the various etiologies of the liver dysfunction, the etiology of HE is not completely understood. Nevertheless, several mechanisms are known to be associated with the development of HE and elevated serum ammonia seems to be the spark along with other precipitating factors. Precipitating factors can be found in 80% of cases with overt HE12. These precipitants work by increasing the underlying inflammatory milieu, or altering the ammonia threshold, or a combination of the above. The precipitants are listed in the table

**neurotransmission**

Benzodiazepines Continued

Psychoactive drugs Development of

**Hepatocellular damage**

alcohol abuse

hepatocellular carcinoma

**Decreased toxin clearance Altered**

paracentesis

restriction

Diarrhea secondary to laxatives

Vasodilation

Table P-1 Common precipitants of hepatic encephalopathy and the underlying mechanisms

The pathophysiology is based largely on the five organs involved in the ammonia metabolism – gut, muscles, kidneys, liver, and brain13. The gut, kidneys and muscles are involved in the production of ammonia into the blood system. In the gut, ammonia is mainly produced by urease producing gut flora, which cleaves protein enzymatically to ammonia (NH3), and then absorbed into the portal-system through the colon14. In addition, enterocytes contain glutaminase, which converts glutamine to glutamate and ammonia15. The kidneys also express glutaminase and are involved in ammonia production during acidbase balance and dehydration16. With intense exercise or seizure, ammonia is produced in

Normally, ammonia is metabolized to urea in the liver for renal clearance. Eighty to ninety percent of ammonia enters the urea cycle via the liver and is ultimately cleared via the kidneys. Ammonia clearance also occurs within the kidneys, skeletal muscles, and brain. Ten to twenty percent of ammonia is metabolized by the skeletal muscles and brain via glutamine synthetase. Glutamine synthetase is the enzyme responsible for the condensation of glutamate and ammonia to form glutamine. In patients with cirrhosis, muscle wasting is

Dehydration Abdominal

Constipation Fluid

GI bleed Diuresis

Azotemia Hypotension Bleeding

Hypokalemia Portal-systemic shunts

Infection Anemia

**2. Pathophysiology**

below (Table P-1).

Excess dietary protein

**Increased Nitrogen load**

Blood transfusion

**2.1 Ammonia**

the skeletal muscles14.

minimal HE depending on symptoms and presentation. Persistent HE is subdivided into mild, severe, and treatment-dependent. Persistent HE presents with cognitive defects that negatively affect social and occupational functioning. The differences between mild and severe persistent HE depend on the West Haven Criteria. Mild persistent HE is present when a patient has met the persistent HE definition as well as having West Haven grade one, whereas severe persistent HE is present with grade two, three, or four of the West Haven Criteria. Treatment-dependent persistent HE implies that overt symptoms develop when treatment stops10. Episodic HE is subdivided into recurrent, precipitated, and spontaneous. Episodic is essentially viewed as delirium secondary to a general medical condition, with delirium defined as a disturbance of consciousness that is accompanied by a change in cognition that cannot be accounted for by a pre-existing or evolving dementia. Recurrent episodic HE is defined as having had two or more episodes in one year. Precipitated episodic HE is caused by an identifiable precipitant which led to the HE episode. These precipitants are listed in Table P-1. Spontaneous episodic HE is diagnosed only if no precipitant can be identified and all other causes of mental status alteration have been ruled out. Minimal HE is diagnosed by specialized tests due to the subtlety of its presentation. The most commonly used clinical categorization of HE is minimal and overt HE. Overt HE includes both persistent and episodic HE. But neither the World Congress of Gastroenterology nor the minimal and overt HE Classification systems are scientific or precise enough to offer a clear idea of the patient's clinical condition.

Due to the inconsistencies between HE severity scores, Bajaj and Cordoba created the Spectrum of Neurocognitive Impairment in Cirrhosis (SONIC) to eliminate the phrasing of minimal, overt and normal, as well as the scoring system of West Haven Criteria7. In utilizing a spectrum, the physician can follow the patient's mental status on a day-to-day basis with standardization in place to allow all providers to understand the clinical course of the patient. Although this spectrum was created to eliminate other severity classifications, the use of both West Haven Criteria and minimal/overt HE descriptions is widely practiced. Other scoring systems have been used in small studies such as the HE Scoring Algorithm (HESA)11 and clinical hepatic encephalopathy staging scale (CHESS)162 but they have not been tested in large, multicenter trials 7.

Used with permission from *Alimentary Pharmacology and Therapies* "Modern management of Hepatic Encephalopathy" 2010.

Table I-1. West Haven Criteria for Hepatic Encephalopathy

minimal HE depending on symptoms and presentation. Persistent HE is subdivided into mild, severe, and treatment-dependent. Persistent HE presents with cognitive defects that negatively affect social and occupational functioning. The differences between mild and severe persistent HE depend on the West Haven Criteria. Mild persistent HE is present when a patient has met the persistent HE definition as well as having West Haven grade one, whereas severe persistent HE is present with grade two, three, or four of the West Haven Criteria. Treatment-dependent persistent HE implies that overt symptoms develop when treatment stops10. Episodic HE is subdivided into recurrent, precipitated, and spontaneous. Episodic is essentially viewed as delirium secondary to a general medical condition, with delirium defined as a disturbance of consciousness that is accompanied by a change in cognition that cannot be accounted for by a pre-existing or evolving dementia. Recurrent episodic HE is defined as having had two or more episodes in one year. Precipitated episodic HE is caused by an identifiable precipitant which led to the HE episode. These precipitants are listed in Table P-1. Spontaneous episodic HE is diagnosed only if no precipitant can be identified and all other causes of mental status alteration have been ruled out. Minimal HE is diagnosed by specialized tests due to the subtlety of its presentation. The most commonly used clinical categorization of HE is minimal and overt HE. Overt HE includes both persistent and episodic HE. But neither the World Congress of Gastroenterology nor the minimal and overt HE Classification systems are scientific or

Due to the inconsistencies between HE severity scores, Bajaj and Cordoba created the Spectrum of Neurocognitive Impairment in Cirrhosis (SONIC) to eliminate the phrasing of minimal, overt and normal, as well as the scoring system of West Haven Criteria7. In utilizing a spectrum, the physician can follow the patient's mental status on a day-to-day basis with standardization in place to allow all providers to understand the clinical course of the patient. Although this spectrum was created to eliminate other severity classifications, the use of both West Haven Criteria and minimal/overt HE descriptions is widely practiced. Other scoring systems have been used in small studies such as the HE Scoring Algorithm (HESA)11 and clinical hepatic encephalopathy staging scale (CHESS)162 but they have not

**Stage Consciousness Intellect/behavior Neurological findings**

Shortened attention span, impaired addition/subtraction

4 Coma Coma Decerebrate posturing Used with permission from *Alimentary Pharmacology and Therapies* "Modern management of Hepatic

Mild asterixis or tremor

Obvious asterixis; slurred

Muscular rigidity, clonus,

speech

hyperreflexia

0 Normal Normal Normal exam

2 Lethargic Disoriented; inappropriate

3 Somnolent Gross disorientation; bizarre

Table I-1. West Haven Criteria for Hepatic Encephalopathy

behavior

behavior

precise enough to offer a clear idea of the patient's clinical condition.

been tested in large, multicenter trials 7.

1 Mild lack of

Encephalopathy" 2010.

awareness

### **2. Pathophysiology**

Due to the various etiologies of the liver dysfunction, the etiology of HE is not completely understood. Nevertheless, several mechanisms are known to be associated with the development of HE and elevated serum ammonia seems to be the spark along with other precipitating factors. Precipitating factors can be found in 80% of cases with overt HE12. These precipitants work by increasing the underlying inflammatory milieu, or altering the ammonia threshold, or a combination of the above. The precipitants are listed in the table below (Table P-1).

Table P-1 Common precipitants of hepatic encephalopathy and the underlying mechanisms

#### **2.1 Ammonia**

The pathophysiology is based largely on the five organs involved in the ammonia metabolism – gut, muscles, kidneys, liver, and brain13. The gut, kidneys and muscles are involved in the production of ammonia into the blood system. In the gut, ammonia is mainly produced by urease producing gut flora, which cleaves protein enzymatically to ammonia (NH3), and then absorbed into the portal-system through the colon14. In addition, enterocytes contain glutaminase, which converts glutamine to glutamate and ammonia15. The kidneys also express glutaminase and are involved in ammonia production during acidbase balance and dehydration16. With intense exercise or seizure, ammonia is produced in the skeletal muscles14.

Normally, ammonia is metabolized to urea in the liver for renal clearance. Eighty to ninety percent of ammonia enters the urea cycle via the liver and is ultimately cleared via the kidneys. Ammonia clearance also occurs within the kidneys, skeletal muscles, and brain. Ten to twenty percent of ammonia is metabolized by the skeletal muscles and brain via glutamine synthetase. Glutamine synthetase is the enzyme responsible for the condensation of glutamate and ammonia to form glutamine. In patients with cirrhosis, muscle wasting is

Hepatic Encephalopathy 125

hyperammonemia to help in detoxification of ammonia by skeletal muscles. Chronic liver disease and portal-systemic shunts are characterized by reduced levels of BCAA32. Aromatic amino acids are associated with an altered BBB, due to the transportation of glutamine out of the astrocytes which brings AAA into the cells. The imbalance may inhibit normal neurotransmitters such as dopamine, serotonin, and norepinephrine 33, 34 or hinder their synthesis35. This change in concentration has led to treatment options involving BCAA.

Because of the uncertainty surrounding all of the events in HE, a great deal of substances have been observed to be elevated or reduced with HE episodes. GABA, translocator protein 18-kDa (TSPO) receptors, endogenous benzodiazepine, glutamate receptors, serotonin, catecholamines, melatonin, and histamine, which all have a role in cognitive

The GABA-benzodiazepine neurotransmitter system has been implicated in HE pathogenesis on a number of levels. The GABA receptors were once thought to be a major factor in the development of HE; however the receptors have not been shown to be more numerous or active in patients with HE. In the clinical setting, patients with liver failure are more sensitive to the sedative effects of benzodiazepines than those without liver failure. In rat models, ROS and reactive nitrogen species (RNS) are enhanced in the presence of benzodiazepines30, 37. Antagonists to GABA-benzodiazepine receptor complex administered to rats with mild to severe hepatic encephalopathy produced a transient improvement in clinical status38. Neurosteroids, which are metabolites synthesized by cholesterol or steroid precursors, have also been associated with the GABA-A receptors. Neurosteroids are positive allosteric modulators of GABA-A receptor, thus increasing the GABAergic tone. The increased GABAergic tone has been associated with the reduced oxygen requirements and subsequent reduced blood flow and metabolism in the brain39. Endogenous benzodiazepines, which have also been involved with the activation GABA-Aergic neurotransmission, have been identified with contributing to HE. The concentrations of these endogenous benzodiazepines have been directly correlated with the severity of HE in

animal models, but the role in humans has not be completely elucidated40.

In patients with HE, translocator protein 18-kDa (TSPO) (formerly known as peripheral-type benzodiazepine receptor (PTBR)) is upregulated in microglial cells that are activated by inflammation41. This receptor is responsible for increasing the neurosteroid concentrations that stimulates the GABAergic tone as described above. The TSPO is activated by increases in ammonia and manganese40, 42. Ammonia's presence as an activator of TSPO seems appropriate. Manganese has a role as well. Serum manganese levels are not elevated in HE, but deposits in the basal ganglia have been seen on MRI. Manganese toxicity has similar clinical manifestations as HE, with the addition of Parkinsonian symptoms, which may or

Glutamate receptors have been implicated mainly through the effects of the glutamate, ROS and RNS. As part of the "Trojan Horse Hypothesis," ammonia is thought to induce oxidation when produced from glutamine within the mitochondria of astrocytes. The RNA oxidation induces N-methyl D-aspartic acid (NMDA) activation43. NMDA receptors are

However, clinical trials of specialized BCAA formulas have yielded mixed results36.

**2.4 Neurologic alterations**

may not be present in HE21, 22.

function, have been altered during HE.

common, thus limiting the ability of skeletal muscles to clear ammonia. The kidney expresses glutamine synthetase and is capable of increasing ammonia metabolism and excretion17. The shunting of blood (physiologic or iatrogenic) away from the liver decreases the ammonia metabolism in the liver, and increases systemic circulatory ammonia levels 16, 17.

In the brain, astrocytes are the only brain cells that can metabolize ammonia into glutamine via glutamine synthetase18.  They also have the power to regenerate, which allows them to aid in repairing neuronal tissue19. When ammonia levels are elevated in the brain, glutamine levels are elevated which leads to an influx of water and subsequent edema. With chronic exposure to ammonia as well as manganese, astrocytes can undergo a morphologic change to Alzheimer type 2 astrocytosis characterized by cell swelling, large nuclei, prominent nucleoli, marginated chromatin, and the inability of cells to function20, 21, 22. The swelling of the astrocytes can cause cerebral edema and intracranial hypertension, which leads to global effects on the brain including agitation to seizures14, 23-25. This cerebral edema has been demonstrated on MRI by reduced magnetization transfer ratios in patients with overt HE 26. The dysfunction of the astrocytes can lead to permanent damage of the brain. The permanent neurologic damage was seen in patients who received a liver transplant after recurrent episodes of overt HE. The changes included decreased brain volume seen on MRI, loss of the N-acetylaspartate/Creatine-phosphocreatine neuronal marker, and gross motor dysfunction27. When acute elevation of arterial ammonia to levels greater than 200 Umol/L occurs, cerebral autoregulation is lost and cerebral edema and intracranial hypertension may result in herniation24, 25.

#### **2.2 Inflammation**

High levels of ammonia do not cause the symptoms of HE alone; a spark has to be present – inflammation. Inflammatory markers are elevated in patients with HE and they can affect the liver and neurologic functions. Inflammatory markers were present in a number of studies, and they are relevant in the presence of all types of HE. Inflammatory markers including C-reactive protein, white blood cell levels, and interleukin-6 are higher in patients with minimal HE than those without minimal HE28. In overt HE, cytokines are released by the astrocytes in response to ammonia-related injury.  The permeability of the BBB to ammonia increases with increasing severity of liver disease29. Over-active neutrophils have been associated with HE and exhibit excessive degranulation and release of reactive oxygen species (ROS). The cytokines increase permeability of ammonia to the BBB. Ammonia swells the astrocytes with osmotic stress, and oxidative and nitrosative stress may cause apoptosis30. Thus, ammonia and the inflammation alter the environment of the astrocytes and BBB in a synergistic fashion to create a spectrum of neurologic changes31.

#### **2.3 Amino acids**

An elevation in aromatic amino acids to branched chain amino acids (BCAA) ratio is present in a large portion of patients with cirrhosis and HE. Aromatic amino acids (AAA) are elevated relative to baseline in patients with HE. BCAA are utilized more in the presence of

common, thus limiting the ability of skeletal muscles to clear ammonia. The kidney expresses glutamine synthetase and is capable of increasing ammonia metabolism and excretion17. The shunting of blood (physiologic or iatrogenic) away from the liver decreases the ammonia

In the brain, astrocytes are the only brain cells that can metabolize ammonia into glutamine via glutamine synthetase18.  They also have the power to regenerate, which allows them to aid in repairing neuronal tissue19. When ammonia levels are elevated in the brain, glutamine levels are elevated which leads to an influx of water and subsequent edema. With chronic exposure to ammonia as well as manganese, astrocytes can undergo a morphologic change to Alzheimer type 2 astrocytosis characterized by cell swelling, large nuclei, prominent nucleoli, marginated chromatin, and the inability of cells to function20, 21, 22. The swelling of the astrocytes can cause cerebral edema and intracranial hypertension, which leads to global effects on the brain including agitation to seizures14, 23-25. This cerebral edema has been demonstrated on MRI by reduced magnetization transfer ratios in patients with overt HE 26. The dysfunction of the astrocytes can lead to permanent damage of the brain. The permanent neurologic damage was seen in patients who received a liver transplant after recurrent episodes of overt HE. The changes included decreased brain volume seen on MRI, loss of the N-acetylaspartate/Creatine-phosphocreatine neuronal marker, and gross motor dysfunction27. When acute elevation of arterial ammonia to levels greater than 200 Umol/L occurs, cerebral autoregulation is lost and cerebral edema and

High levels of ammonia do not cause the symptoms of HE alone; a spark has to be present – inflammation. Inflammatory markers are elevated in patients with HE and they can affect the liver and neurologic functions. Inflammatory markers were present in a number of studies, and they are relevant in the presence of all types of HE. Inflammatory markers including C-reactive protein, white blood cell levels, and interleukin-6 are higher in patients with minimal HE than those without minimal HE28. In overt HE, cytokines are released by the astrocytes in response to ammonia-related injury.  The permeability of the BBB to ammonia increases with increasing severity of liver disease29. Over-active neutrophils have been associated with HE and exhibit excessive degranulation and release of reactive oxygen species (ROS). The cytokines increase permeability of ammonia to the BBB. Ammonia swells the astrocytes with osmotic stress, and oxidative and nitrosative stress may cause apoptosis30. Thus, ammonia and the inflammation alter the environment of the astrocytes and BBB in a synergistic fashion to

An elevation in aromatic amino acids to branched chain amino acids (BCAA) ratio is present in a large portion of patients with cirrhosis and HE. Aromatic amino acids (AAA) are elevated relative to baseline in patients with HE. BCAA are utilized more in the presence of

metabolism in the liver, and increases systemic circulatory ammonia levels 16, 17.

intracranial hypertension may result in herniation24, 25.

create a spectrum of neurologic changes31.

**2.2 Inflammation**

**2.3 Amino acids**

hyperammonemia to help in detoxification of ammonia by skeletal muscles. Chronic liver disease and portal-systemic shunts are characterized by reduced levels of BCAA32. Aromatic amino acids are associated with an altered BBB, due to the transportation of glutamine out of the astrocytes which brings AAA into the cells. The imbalance may inhibit normal neurotransmitters such as dopamine, serotonin, and norepinephrine 33, 34 or hinder their synthesis35. This change in concentration has led to treatment options involving BCAA. However, clinical trials of specialized BCAA formulas have yielded mixed results36.

#### **2.4 Neurologic alterations**

Because of the uncertainty surrounding all of the events in HE, a great deal of substances have been observed to be elevated or reduced with HE episodes. GABA, translocator protein 18-kDa (TSPO) receptors, endogenous benzodiazepine, glutamate receptors, serotonin, catecholamines, melatonin, and histamine, which all have a role in cognitive function, have been altered during HE.

The GABA-benzodiazepine neurotransmitter system has been implicated in HE pathogenesis on a number of levels. The GABA receptors were once thought to be a major factor in the development of HE; however the receptors have not been shown to be more numerous or active in patients with HE. In the clinical setting, patients with liver failure are more sensitive to the sedative effects of benzodiazepines than those without liver failure. In rat models, ROS and reactive nitrogen species (RNS) are enhanced in the presence of benzodiazepines30, 37. Antagonists to GABA-benzodiazepine receptor complex administered to rats with mild to severe hepatic encephalopathy produced a transient improvement in clinical status38. Neurosteroids, which are metabolites synthesized by cholesterol or steroid precursors, have also been associated with the GABA-A receptors. Neurosteroids are positive allosteric modulators of GABA-A receptor, thus increasing the GABAergic tone. The increased GABAergic tone has been associated with the reduced oxygen requirements and subsequent reduced blood flow and metabolism in the brain39. Endogenous benzodiazepines, which have also been involved with the activation GABA-Aergic neurotransmission, have been identified with contributing to HE. The concentrations of these endogenous benzodiazepines have been directly correlated with the severity of HE in animal models, but the role in humans has not be completely elucidated40.

In patients with HE, translocator protein 18-kDa (TSPO) (formerly known as peripheral-type benzodiazepine receptor (PTBR)) is upregulated in microglial cells that are activated by inflammation41. This receptor is responsible for increasing the neurosteroid concentrations that stimulates the GABAergic tone as described above. The TSPO is activated by increases in ammonia and manganese40, 42. Ammonia's presence as an activator of TSPO seems appropriate. Manganese has a role as well. Serum manganese levels are not elevated in HE, but deposits in the basal ganglia have been seen on MRI. Manganese toxicity has similar clinical manifestations as HE, with the addition of Parkinsonian symptoms, which may or may not be present in HE21, 22.

Glutamate receptors have been implicated mainly through the effects of the glutamate, ROS and RNS. As part of the "Trojan Horse Hypothesis," ammonia is thought to induce oxidation when produced from glutamine within the mitochondria of astrocytes. The RNA oxidation induces N-methyl D-aspartic acid (NMDA) activation43. NMDA receptors are

Hepatic Encephalopathy 127

A large nitrogen load can precipitate an episode of HE. Excess dietary protein, constipation, and hypokalemia are all intake/output related, and can be treated with relative ease. Hypokalemia's effects stem from altering the BBB, and allowing more ammonia to cross. GI bleeding can also precipitate an episode of HE. GI bleeding leads to an excess of ammonia in the blood by digesting and absorbing proteins from the breakdown of red blood cells in the intestines. In addition, GI bleeding leads to the production of ammonia from the kidney resulting in hyperammonemia as well as potential hypovolemia17, 50. Blood transfusions can be a less obvious cause, but must be considered as a potential precipitating event in HE,

Infection is a common contributor to HE. Infection or sepsis is usually apparent with a combination of increased temperature, white blood cell count, heart rate and respiratory rate. Cirrhotics are also viewed as functionally immunocompromised, therefore, their risk of infection is increased31. Because infection is such a common cause of HE, it is standard of care to evaluate all patients with HE with an infection workup including blood and urine

Decreased toxin clearance is generally associated with hypovolemia (dehydration, hypotension, or anemia) and portal-systemic shunting (either iatrogenic or spontaneous). Shunting of blood away from the liver bypasses hepatic cells and minimizes the clearance of toxins51. Dehydration and anemia, which are usually associated with hypotension, can lead to ineffective clearance of toxins by the kidneys. On occasion, hypotension can be due to systemic vasodilation which has the same result of ineffective toxin clearance. The lack of clearance in all of these processes leads to increased levels of toxins, most notably ammonia. As noted in the astrocyte physiology, neurotransmission is vital to neurologic functioning. Altered neurotransmission is known to be a precipitating factor in HE. Patients placed on benzodiazepines or any psychoactive drug may react drastically for separate, yet related reasons. Endogenous benzodiazepines are elevated during HE, and increasing the concentration of these would severely affect the patient40. With the hepatocytes damaged from the liver disease, blood shunted away from the liver, and various transporter proteins downregulated as a result of the liver disease, drugs affecting the cognitive function of a patient will have a more pronounced effect including stimulants (caffeine, amphemtamines,

Although hepatocellular damage is already present, in certain situations it can be worsened. Continued abuse of alcohol may cause worsening hepatic function, which can lead to a spontaneous shunt and a buildup of toxins in the blood and brain. Also, the development of

The diagnosis of overt HE is generally made by the presence of clinical signs and symptoms, elevated ammonia levels, and the absence of other possible causes of altered mental status. The signs and symptoms seen early are alterations in sleeping patterns, which can progress to somnolence and on to obtundation48. Some patients may become more agitated usually occurring in Type A HE54-56. Types B and C HE presentations are more associated with neuroinhibitory symptoms57-59. Nevertheless, the approach to anyone suspected of having

hepatocellular carcinoma in the setting of cirrhosis may worsen the patient's status53.

especially after an acute GI bleed.

cultures, chest x-ray, skin exam and diagnostic paracentesis4.

methylphenidate) and depressants (sedatives, narcotics)52.

**3. Diagnosis**