Initial cerebral hyperaemia after the hypoxic-ischemic insult is followed by delayed cerebral hypoperfusion. A steady decrease of BFV 12 hours after asphyxia has been described in infants (Ilves et al., 2004; Shadid et al., 1998; van Bel et al., 1998) and in animal models (Kangström et al., 1983). It has been speculated that the delayed hypoperfusion may add a secondary ischaemic insult to the tissue, especially if the reduction in BFV is not matched to the metabolic rate (Kangström et al., 1983). The severity of posthypoxic hypoperfusion increases with the increasing duration of a preceding cerebral ischemia (Kangström et al., 1983). Among infants with severe birth asphyxia, babies with the severest stage of HIE demonstrated the greatest decrease in BFV (van Bel et al., 1998). We have shown that some asphyxiated infants mostly with moderate HIE have extremely low cerebral BFV velocities (below 3SD) with a high RI during the first day of life which is associated with poor prognosis (Ilves et al., 2004, 2009a, 2009b)(Figure 2d). This delayed postasphyxial cerebral hypoperfusion could be related to an excess of vasoconstrictor molecules (Fellman & Raivio, 1997). Low cerebral blood volume during the first 28 days of life was described in a small group of infants probably with mild to moderate HIE, developing cerebral paralysis later

Several authors have reported high BFV and significantly lowered RI in infants with severe HIE at the age of 24-72 h (Levene et al., 1989; Bennhagen et al., 1998; Ilves et al., 2009 a, 2009b) (Figure 2f). BFV has been recorded higher in infants with permanent brain damage

damage during reperfusion (Fellman & Raivio, 1997; Rosenberg, 1986).

**5.2.1 Initial cerebral hyperaemia**

(Kangström et al., 1983).

(Fukuda et al., 2008).

**5.2.2 Delayed cerebral hypoperfusion**

**5.2.3 Delayed cerebral hyperperfusion**

during the first days of life (Pryds, 1991; Ilves et al., 2009 a, 2009b). Severe increase in cerebral BFV and the decrease in RI take place in asphyxiated infants with severe HIE and a poor prognosis by the second half of the first day, being most severe during the first 3 days (Bennhagen et al., 1998; Ilves et al., 2009a; Meek et al., 1999; Pryds et al., 1990). The maximum BFV values are registered at the age of 36-71 h (Ilves et al., 2009a) decreasing gradually by the age of 1 week (Figure 1). However, in very severe cases with a poor prognosis high BFV is seen already at the age of 12h or ealier suggesting a very short therapeutic window in severely asphyxiated infants (Ilves et al., 2009a). Animal models have also shown that initial posthypoxic hypoperfusion is followed by delayed vasodilatation, increased BFV and cerebral energy failure 24-72 h after the hypoxic-ischemic insult (Lorek et al., 1994). In this situation, dissociation exists between the cerebral metabolic rate and the over-abundant BFV relative to the metabolic needs of the brain tissue, the socalled luxury perfusion (Levene et al., 1989). Markedly high BFV despite isoelelctric EEG activity is found in these infants (Pryds, 1991). The BFV was higher, but the cross-brain oxygen extraction was lower in asphyxiated infants who died, compared to the neonates who survived with a normal neurologic outcome (Frewen et al., 1991). Delayed hyperaemia often occurs as a focal phenomenon, but may also be generalised (Levene et al., 1989).

Fig. 1. Mean cerebral blood velocity ( TAV) in a anterior cerebral artery infants with HIE with HIE 0 (n=115 infants); HIE I+II (n=58infants); HIE III (n=25infants); ∗p < 0.05 HIE III vs. HIE I+II; ∗∗p < 0.001 HIE III vs. HIE I+II; §p < 0.05 HIE III versus HIE 0; §§p < 0.001 HIE III versus HIE

In 1986, Archer et al. (Archer, et al., 1986) introduced the cerebral vascular resistance index (RI) for predicting clinical outcome from 24 h of age in the infants with moderate or severe HIE (Figure 2f). In severe HIE patients the RI below 0.55 had a positive predictive value (PPV) for death or disability of 75% and a negative predictive value (NPV) of 100%. Bennhagen and co-workers have found the RI increased in infants with HIE during the first

Sonographic Changes in Hypoxic-Ischaemic Encephalopathy 77

positive predictor of poor outcome as reported earlier in normothermic infants. These findings mean that infants, who would have been predicted to have poorer outcome at normothermia, have better outcome treated when cooled. A low RI is significantly less predictive of poor outcome during hypothermia than normothermia. The lower PPV of RI may be because hypothermia affects cerebral vasculature or protects the brain solely at a molecular and cellular level. Infants, who would have been predicted from their RI to have poorer outcome at normothermia, have better outcome when cooled" (Elstad et al., 2011). RI should never be used for prediction alone; it is only one piece of information to be put into the clinical puzzle. However, as ultrasound Doppler is safe, cheap and readily available, RI measurement is recommended on day 2 (24–48 h after birth) and three (48–72 h) for infants

The animal model using contrast-enhanced ultrasound (CEUS) and MRI shows that both can detect an early temporal evolution of cerebral perfusion in perinatal hypoxia and resuscitation, reversible after 7 hours (de Lange et al., 2011). Hyperoxic resuscitation caused early decreased cerebral perfusion, not present in the normoxic group. These findings show that the combined use of CEUS can provide important diagnostic information and give new

with HIE treated with hypothermia as RI is lowest at 48 h" (Elstad et al., 2011).

insights into perinatal vascular hypoxia mechanisms (de Lange et al., 2011).

a b

c d

day of life developing low RI by the second day of life (Bennhagen et al., 1998). In some infants with poor prognosis, the RI is already significantly lower compared to the control group as early as at the age of 2-11.9 h (Ilves et al., 2009a). Although the low RI soon after birth had a poor outcome, the high RI was found in most infants who subsequently had a poor outcome (Eken et al., 1995). RI was independent of the angle between the ultrasound beam and the blood flow in the artery being examined and could be obtained from any intracerebral arter giving a good-quality signal.

The reason for this cerebral hyperaemia and the low RI during the second-third day after asphyxia may be a severe vasoparalysis, a form of irreversible cerebral vascular injury (Levene et al., 1989; Pryds et al., 1990; Meek et al., 1999). In infants with birth asphyxia hyperperfusion is thought to be a sign of permanent brain damage with a poor neurodevelopemental prognosis (Bennhagen et al., 1998; Ilves et al., 2009a; Meek et al., 1999; Pryds et al., 1990). The severity of vasoparalysis and cerebral hyperaemia is thought to correlate with the degree of brain injury and presumably the severity of asphyxia insult (Levene et al., 1989; Pryds et al., 1990). The infants with the poorest neurologic outcome (isoelectric EEG and death) had the highest values for BFV and no cerebrovascular autoregulation or CO2 reactivity; the infants with the burst suppression EEG and moderate to severe brain injury has slightly elevated values of BFV and impaired autoregulation, but a sustained reactivity to Pa CO2 (Pryds et al., 1990). The infants without an evidence of brain injury had normal values for BFV, intact autoregulation and reactivity to PaCO2 (Pryds et al., 1990). The mechanism of such luxury cerebral perfusion following ischaemic brain injury is still unclear. The neuronal disruption causing release of vasoactive substances such as adenosine and lactate, or of excitatory amino acids (Pryds, 1991), irreversible cerebral vascular injury with a complete loss of tone in resistance vessels may play a role in the pathogenesis of delayed hyperaemia (Fellman & Raivio, 1997; Levene et al., 1989; Pryds et al., 1990).

 However, recent studies show that even in the infants with mild /moderate HIE the mean cerebral BFV was higher than in the control group in all the cerebral arteries during the period 36-120 h (Ilves et al., 2009a). Moderately but statistically significantly increased mean cerebral BFV in the infants with mild-moderate HIE from 36 h lasting as late as 7-10 days after asphyxia can indicate the ongoing subacute process of cell damage in these infants. Although only a small number (2 of 58 infants) with moderate HIE developed severe disability (Ilves et al., 2009a) at the age of 18 months, recent data in the long-term follow-up study of the infants with moderate HIE show a high rate of cognitive dysfunctions in these children (Lindström et al., 2008).

All the previously published literature on RI and BFV and the prediction of outcome has been obtained on infants at normal temperature. It is possible that hypothermia will affect the cardiovascular system in the ways that might change RI (Elstad et al., 2011; Thoresen & Whitelaw, 2000). Elstad with cowoorker have described: "Among the cooled infants, the PPV of any RI below 0.55 for poor outcome was only 60%. This is lower than the PPV in any previous studies in infants with HIE treated at normothermia (median value 84%). The initial data show that RI > 0.55 is a good negative predictor, but RI below 0.55 is not as good

day of life developing low RI by the second day of life (Bennhagen et al., 1998). In some infants with poor prognosis, the RI is already significantly lower compared to the control group as early as at the age of 2-11.9 h (Ilves et al., 2009a). Although the low RI soon after birth had a poor outcome, the high RI was found in most infants who subsequently had a poor outcome (Eken et al., 1995). RI was independent of the angle between the ultrasound beam and the blood flow in the artery being examined and could be obtained from any

The reason for this cerebral hyperaemia and the low RI during the second-third day after asphyxia may be a severe vasoparalysis, a form of irreversible cerebral vascular injury (Levene et al., 1989; Pryds et al., 1990; Meek et al., 1999). In infants with birth asphyxia hyperperfusion is thought to be a sign of permanent brain damage with a poor neurodevelopemental prognosis (Bennhagen et al., 1998; Ilves et al., 2009a; Meek et al., 1999; Pryds et al., 1990). The severity of vasoparalysis and cerebral hyperaemia is thought to correlate with the degree of brain injury and presumably the severity of asphyxia insult (Levene et al., 1989; Pryds et al., 1990). The infants with the poorest neurologic outcome (isoelectric EEG and death) had the highest values for BFV and no cerebrovascular autoregulation or CO2 reactivity; the infants with the burst suppression EEG and moderate to severe brain injury has slightly elevated values of BFV and impaired autoregulation, but a sustained reactivity to Pa CO2 (Pryds et al., 1990). The infants without an evidence of brain injury had normal values for BFV, intact autoregulation and reactivity to PaCO2 (Pryds et al., 1990). The mechanism of such luxury cerebral perfusion following ischaemic brain injury is still unclear. The neuronal disruption causing release of vasoactive substances such as adenosine and lactate, or of excitatory amino acids (Pryds, 1991), irreversible cerebral vascular injury with a complete loss of tone in resistance vessels may play a role in the pathogenesis of delayed hyperaemia (Fellman & Raivio, 1997; Levene et al., 1989; Pryds et

Severe increase in the cerebral blood flow velocity and the decrease in RI have been described in infants with severe HIE/ poor outcome (Eken et al., 1995; Ilves et al., 2004, 2009a; Levene et al., 1989; Pryds et al., 1990; Stark et al., 1994). However, recent studies show that even in the infants with mild /moderate HIE the mean cerebral BFV was higher than in the control group in all the cerebral arteries during the period 36-120 h (Ilves et al., 2009a). Moderately but statistically significantly increased mean cerebral BFV in the infants with mild-moderate HIE from 36 h lasting as late as 7-10 days after asphyxia can indicate the ongoing subacute process of cell damage in these infants. Although only a small number (2 of 58 infants) with moderate HIE developed severe disability (Ilves et al., 2009a) at the age of 18 months, recent data in the long-term follow-up study of the infants with moderate HIE

show a high rate of cognitive dysfunctions in these children (Lindström et al., 2008).

All the previously published literature on RI and BFV and the prediction of outcome has been obtained on infants at normal temperature. It is possible that hypothermia will affect the cardiovascular system in the ways that might change RI (Elstad et al., 2011; Thoresen & Whitelaw, 2000). Elstad with cowoorker have described: "Among the cooled infants, the PPV of any RI below 0.55 for poor outcome was only 60%. This is lower than the PPV in any previous studies in infants with HIE treated at normothermia (median value 84%). The initial data show that RI > 0.55 is a good negative predictor, but RI below 0.55 is not as good

intracerebral arter giving a good-quality signal.

al., 1990).

positive predictor of poor outcome as reported earlier in normothermic infants. These findings mean that infants, who would have been predicted to have poorer outcome at normothermia, have better outcome treated when cooled. A low RI is significantly less predictive of poor outcome during hypothermia than normothermia. The lower PPV of RI may be because hypothermia affects cerebral vasculature or protects the brain solely at a molecular and cellular level. Infants, who would have been predicted from their RI to have poorer outcome at normothermia, have better outcome when cooled" (Elstad et al., 2011). RI should never be used for prediction alone; it is only one piece of information to be put into the clinical puzzle. However, as ultrasound Doppler is safe, cheap and readily available, RI measurement is recommended on day 2 (24–48 h after birth) and three (48–72 h) for infants with HIE treated with hypothermia as RI is lowest at 48 h" (Elstad et al., 2011).

The animal model using contrast-enhanced ultrasound (CEUS) and MRI shows that both can detect an early temporal evolution of cerebral perfusion in perinatal hypoxia and resuscitation, reversible after 7 hours (de Lange et al., 2011). Hyperoxic resuscitation caused early decreased cerebral perfusion, not present in the normoxic group. These findings show that the combined use of CEUS can provide important diagnostic information and give new insights into perinatal vascular hypoxia mechanisms (de Lange et al., 2011).

a b

c d

Sonographic Changes in Hypoxic-Ischaemic Encephalopathy 79

Late findings of US include the resolution of the initial findings and the progressive prominence of the ventricles and the extraaxial CSF containing spaces, likely due to atrophy

By the age of the 7 days the size of the ventricles, the interhemispheric fissure and the subarachnoideal space were significantly increased in the infants with a severe HIE/poor prognosis compared to the infants with a mild to moderate HIE or the infants with a normal outcome/mild impairments respectively (Ilves et al., 2009a). By the age of 5 months the progressive enlargement of the size of the ventricles, the interhemispheric fissure and the subarachnoideal space occurred in the infants with a severe HIE/poor prognosis (Ilves et al. 2009a) (Figure 2h). The size of the ventricles and the interhemispheric fissure at the age of 21-159 days was significantly correlated with the severity of HIE and the psychomotor

Multicystic encephalopathy developed in 18 of 25 infants with severe HIE, all had a poor outcome: 10 infants died and eight infants were with severe disability at the age of 18 months. Parenchymal cysts mostly in the frontoparietal region were first seen as early as at the age of 7 days in five infants, all died during the first month. In 12 infants with severe HIE cysts could be visualized between the age of 14-21 days and only in 1 of 18 infants the cysts were first seen after the age of 21 days (Ilves et al., 2009a). Small cysts are no longer visible by the age of 3 months, therefore it seems reasonable to perform US in the infants with a moderate or severe stage of HIE at the age of 1 month in order to detect all the infants

The intensity of the initial insult may determine the mode of cell death resulting in necrosis in severe injury whereas milder insults result in apoptosis (Bonfoco et al., 1995). It is likely that the enlargement of the side ventricles and the appearance of the parenchymal cysts visible already by the age of 7 days in the infants who died can be the signs of rapid cell death and probably represent cell necrosis, which accounts for the significant proportion of

CT and MRI studies indicate the temporal profile of the signs of the brain swelling during the first week of life being most severe 36-72 hours after asphyxia (Rutherford et al., 1995; Yoxall & Weindling, 1998) (Figure 2h). The infants with a severe HIE/poor prognosis and the progressive enlargement of the side ventricles and the subarachnoidal space with the development of parenchymal cysts during the first months of life have also suboptimal head growth during the first months of life (Ilves et al., 2009a). This enlargement of side ventricles progresses during several months (Ilves et al., 2009a). Decrease in the periventricular white matter has been described earlier in MRI studies in the infants older than 3 weeks (Rutherford et al., 1995). Serial head circumference investigations also show that the appearance of microcephaly may be delayed for more than 12 months (Cordes et al., 1994). The findings suggest that cell death can be long-lasting with on-going progressive cell loss days and may be weeks and months after asphyxia. Apoptosis that is aslower process can play a role in the long-lasting brain damage in the infants with severe asphyxia. This can indicate that neuroprotection probably must be lasting more than only first days after

**6. Long-term changes in sonography**

development at the age 18 months.

with cystic degeneration (Ilves et al., 2009a).

the cell loss in asphyxiated infants (Bonfoco et al., 1995).

**6.1 Long-term changes in gray–scale sonography**

and the development of multicyctic encephalopathy.

e f

a) Coronar US image shows ill-defined structures including basal ganglia, and slitlike ventricles at the age of 12 h

b) Magnified sagittal view using linear transducer shows the accentuation of the grey –white matter differentiation with prominent sulci at the age of 12 h

c) Left parasagittal view shows hyperaemia in the region of basal ganglia with power Doppler at the age of 12 h

d) Colour Doppler evaluation shows a low cerebral blood flow velocity with normal resistance in the right anterior cerebral artery at the age of 12 h

e) Coronar US image shows still ill-defined structures with general increase in echogenicty including basal ganglia, and still slitlike ventricles at the age of 3 days

f) Colour Doppler evaluation shows a high cerebral blood flow velocity with low resistance in the left medial cerebral artery at the age of 3 days

g) MRI FLAIR image with pathological signal intensity bilaterally in basal ganglia at the age of 8 days h) Coronar US with moderately enlarged side ventricles and ill-defined basal ganglia at the age of 1 month

i) CT image with atrophy and increased attenuation in basal ganglia at the age of 3 years

Fig. 2. 12 h old girl born at 39 weeks of gestation with a history of perinatal asphyxia after total abruption placenta and the respective Apgar scores 1-2-3 at the age of 1-5-10 minutes with severe HIE who survived with cerebral paralysis, tetraplegia, seizures and bulbar paralysis

#### **6. Long-term changes in sonography**

78 Miscellanea on Encephalopathies – A Second Look

e f

g h i

differentiation with prominent sulci at the age of 12 h

basal ganglia, and still slitlike ventricles at the age of 3 days

right anterior cerebral artery at the age of 12 h

medial cerebral artery at the age of 3 days

age of 12 h

age of 12 h

month

paralysis

a) Coronar US image shows ill-defined structures including basal ganglia, and slitlike ventricles at the

b) Magnified sagittal view using linear transducer shows the accentuation of the grey –white matter

c) Left parasagittal view shows hyperaemia in the region of basal ganglia with power Doppler at the

d) Colour Doppler evaluation shows a low cerebral blood flow velocity with normal resistance in the

e) Coronar US image shows still ill-defined structures with general increase in echogenicty including

f) Colour Doppler evaluation shows a high cerebral blood flow velocity with low resistance in the left

g) MRI FLAIR image with pathological signal intensity bilaterally in basal ganglia at the age of 8 days h) Coronar US with moderately enlarged side ventricles and ill-defined basal ganglia at the age of 1

Fig. 2. 12 h old girl born at 39 weeks of gestation with a history of perinatal asphyxia after total abruption placenta and the respective Apgar scores 1-2-3 at the age of 1-5-10 minutes with severe HIE who survived with cerebral paralysis, tetraplegia, seizures and bulbar

i) CT image with atrophy and increased attenuation in basal ganglia at the age of 3 years

#### **6.1 Long-term changes in gray–scale sonography**

Late findings of US include the resolution of the initial findings and the progressive prominence of the ventricles and the extraaxial CSF containing spaces, likely due to atrophy and the development of multicyctic encephalopathy.

By the age of the 7 days the size of the ventricles, the interhemispheric fissure and the subarachnoideal space were significantly increased in the infants with a severe HIE/poor prognosis compared to the infants with a mild to moderate HIE or the infants with a normal outcome/mild impairments respectively (Ilves et al., 2009a). By the age of 5 months the progressive enlargement of the size of the ventricles, the interhemispheric fissure and the subarachnoideal space occurred in the infants with a severe HIE/poor prognosis (Ilves et al. 2009a) (Figure 2h). The size of the ventricles and the interhemispheric fissure at the age of 21-159 days was significantly correlated with the severity of HIE and the psychomotor development at the age 18 months.

Multicystic encephalopathy developed in 18 of 25 infants with severe HIE, all had a poor outcome: 10 infants died and eight infants were with severe disability at the age of 18 months. Parenchymal cysts mostly in the frontoparietal region were first seen as early as at the age of 7 days in five infants, all died during the first month. In 12 infants with severe HIE cysts could be visualized between the age of 14-21 days and only in 1 of 18 infants the cysts were first seen after the age of 21 days (Ilves et al., 2009a). Small cysts are no longer visible by the age of 3 months, therefore it seems reasonable to perform US in the infants with a moderate or severe stage of HIE at the age of 1 month in order to detect all the infants with cystic degeneration (Ilves et al., 2009a).

The intensity of the initial insult may determine the mode of cell death resulting in necrosis in severe injury whereas milder insults result in apoptosis (Bonfoco et al., 1995). It is likely that the enlargement of the side ventricles and the appearance of the parenchymal cysts visible already by the age of 7 days in the infants who died can be the signs of rapid cell death and probably represent cell necrosis, which accounts for the significant proportion of the cell loss in asphyxiated infants (Bonfoco et al., 1995).

CT and MRI studies indicate the temporal profile of the signs of the brain swelling during the first week of life being most severe 36-72 hours after asphyxia (Rutherford et al., 1995; Yoxall & Weindling, 1998) (Figure 2h). The infants with a severe HIE/poor prognosis and the progressive enlargement of the side ventricles and the subarachnoidal space with the development of parenchymal cysts during the first months of life have also suboptimal head growth during the first months of life (Ilves et al., 2009a). This enlargement of side ventricles progresses during several months (Ilves et al., 2009a). Decrease in the periventricular white matter has been described earlier in MRI studies in the infants older than 3 weeks (Rutherford et al., 1995). Serial head circumference investigations also show that the appearance of microcephaly may be delayed for more than 12 months (Cordes et al., 1994). The findings suggest that cell death can be long-lasting with on-going progressive cell loss days and may be weeks and months after asphyxia. Apoptosis that is aslower process can play a role in the long-lasting brain damage in the infants with severe asphyxia. This can indicate that neuroprotection probably must be lasting more than only first days after

Sonographic Changes in Hypoxic-Ischaemic Encephalopathy 81

the damaged cells in the cases of severe brain damage. The only published case report, following longitudinal changes in cerebral metabolism in an infant with HIE and subsequent cerebral palsy, has demonstrated transient hypermetabolism in the neonatal period followed by severe hypometabolism later during childhood (Batista et al., 2007). More longitudinal data about cerebral blood flow and metabolism is needed to understand the causes of long term low cerebral blood flow velocities in infants with a severe HIE/poor

Although the central nervous system is disturbed in 70% of infants after severe birth asphyxia (Martin-Ancel et al., 1995), up to 80-90% of infants develop disturbances in other organs (Martin-Ancel et al., 1995; Shah et al., 2004; Wayenberg et al., 1998). The interruption of the placental blood flow during labour and the decompensation of the circulatory responses lead to systemic hypotension and ischemia in different organs. Redistribution of the blood during asphyxia is the major protective mechanism in order to maintain the perfusion of vital organs such as the brain, heart and adrenal glands, but it causes ischemic damage to the visceral organs like kidneys and gut (Perlman, 2006; Stola & Perlman, 2008). Early BFV changes have been documented in critically ill infants following birth asphyxia in the cerebral (Bennhagen et al., 1998; Ilves, et al., 2009b), renal (RA) (Ilves et al., 2009b; Luciano et al., 1998), superior mesenteric arteries (SMA) (Ilves et al., 2009b; Koc et al., 1998)

Different patterns of post-injury BFV changes exist in the visceral arteries compared to the cerebral arteries in asphyxiated infants with HIE. The mean BFV in the SMA and CA (but not in the RA) increased in the infants with mild-moderate HIE during the first 12 h after asphyxia (Ilves et al., 2009a, 2009b). The reperfusion of ischemic intestine and gastric mucosa is characterised by an initial hyperaemia with ensuing mucosal repair, as shown in animal models (Meleagros et al., 1994). The increase in BFV, seen in the SMA and CA but not in the RA during the first hours after asphyxia, can be the compensatory hyperaemia in the gastrointestinal tract, stomach and liver in the infants with mildmoderate HIE. Such differences in the compensatory capabilities in the RA, SMA and CA can explain the differences in the frequency of severe organ failure found in asphyxiated infants. Renal failure is found to develop more often in 40-57% of asphyxiated infants compared to a lower rate (30%) of gastrointestinal complications in asphyxiated term infants; liver failure is a rare complication in the infants with severe HIE (Martin-Ancel et

The lack of hyperaemia in the SMA and CA and a decrease in BFV in the RA already during the first hours after asphyxia in severe HIE infants, despite vasoactive treatment and normal BP shows decreased compensatory capabilities in the infants with severe HIE to the restore blood flow in the visceral arteries. Extremely low BFV in all the visceral arteries was found during the first day in infants with a very long resuscitation period and the fatal outcome. These infants had normal blood pressure but a very high BFV in the cerebral arteries and a very low BFV in the visceral arteries already during the first day of life with the development of severe HIE, severe renal, gastrointestinal and hepatic failure as well as cardiac failure. Animal models have indicated that reperfusion is the main mechanism of injury after intestinal or renal ischemia; however, the post-ischemic

prognosis months after birth asphyxia.

or in CA (Ilves et al., 2009b).

al., 1995; Perlman et al., 1989).

**6.3 US and Doppler findings in visceral organs**

asphyxia. Therapeutic hypothermia for moderate to severe HIE's during the first days after asphyxia is currently the only clinically proven treatment for infants with neonatal asphyxia (Hoehn et al., 2008). The potential strategies to prevent or reduce reperfusion injury in asphyxiated infants probably need to include the interventions that target both processes: cell necrosis during the first days after asphyxia and apoptosis on going probably during the longer period after asphyxia.

#### **6.2 Long-term changes in Doppler sonography**

In normal infants and the infants with a mild/moderate HIE or good prognosis, steady increase in the mean cerebral BFV and the decrease in RI occurred in all the cerebral arteries during the first months of life (Ilves et al., 2008, 2009a; Kojo et al., 1996; Mercuri et al., 2000), probably reflecting the increasing cerebral blood flow during the first year of life. The infants in the control group and the infants with a mild/moderate HIE or good prognosis also showed steady head growth with no significant differences in the head circumference or the ventricle size between these groups during the first months of life. The steady increase in cerebral BFV in healthy infants appears to reflect the rising metabolic demand of the growing brain during the neonatal period (Kelner et al., 2003). The increase in blood flow has been shown during the first year of life, the cause of which can be rapid myelination and the explosive increase of the synapses with decrease in nerve cell density (Takahashi et al., 1999). The increasing demand for metabolic fuels during the first months after birth is found in the studies investigating cerebral glucose consumption using positron emission tomography (PET) and measuring cerebral oxygen consumption with NIRS (Chugani et al., 1986; Kinnala et al., 1996; Yoxall et al., 1998). This extreme increase in the mean BFV in infants with a severe HIES/poor outcome is temporary and the cerebral BFV gradually decreases after the first week of life (Ilves et al., 2009a). The findings are consistent with the studies of the cerebral glucose metabolism measured by PET in term infants with hypoxic-ischemic encephalopathy, showing hypermetabolism during the acute period 2-5 days after birth asphyxia (Blennow et al., 1995) and lower metabolism during the subacute period (at the age of 4-24 days) after asphyxia (Thorngren-Jerneck et al., 2001).

Such steady increase of the mean BFV is not found in infants with a severe HIE/poor prognosis during the first months after asphyxia (Figure 1). After the extremely high cerebral BFV during the first days of life significantly lower mean cerebral BFV develops during the first months after asphyxia in severe HIE infants.

It is not known whether this decrease in the mean BFV in infants with a severe HIE/poor prognosis is caused only by the low brain volume or whether these infants have lower metabolism or because of both problems. Severe HIE infants had a low head circumference with wide liquor spaces and hence the low brain volume and therefore the required cerebral BFV to fulfil energy requirements for the damaged decreased cerebral parenchyma can be lower. Such decreased brain volume probably no longer needs a normal blood flow. It is also possible that the requirement for energetic fuel is low because of the low metabolism in

asphyxia. Therapeutic hypothermia for moderate to severe HIE's during the first days after asphyxia is currently the only clinically proven treatment for infants with neonatal asphyxia (Hoehn et al., 2008). The potential strategies to prevent or reduce reperfusion injury in asphyxiated infants probably need to include the interventions that target both processes: cell necrosis during the first days after asphyxia and apoptosis on going probably during the

In normal infants and the infants with a mild/moderate HIE or good prognosis, steady increase in the mean cerebral BFV and the decrease in RI occurred in all the cerebral arteries during the first months of life (Ilves et al., 2008, 2009a; Kojo et al., 1996; Mercuri et al., 2000), probably reflecting the increasing cerebral blood flow during the first year of life. The infants in the control group and the infants with a mild/moderate HIE or good prognosis also showed steady head growth with no significant differences in the head circumference or the ventricle size between these groups during the first months of life. The steady increase in cerebral BFV in healthy infants appears to reflect the rising metabolic demand of the growing brain during the neonatal period (Kelner et al., 2003). The increase in blood flow has been shown during the first year of life, the cause of which can be rapid myelination and the explosive increase of the synapses with decrease in nerve cell density (Takahashi et al., 1999). The increasing demand for metabolic fuels during the first months after birth is found in the studies investigating cerebral glucose consumption using positron emission tomography (PET) and measuring cerebral oxygen consumption with NIRS (Chugani et al., 1986; Kinnala et al., 1996; Yoxall et al., 1998). This extreme increase in the mean BFV in infants with a severe HIES/poor outcome is temporary and the cerebral BFV gradually decreases after the first week of life (Ilves et al., 2009a). The findings are consistent with the studies of the cerebral glucose metabolism measured by PET in term infants with hypoxic-ischemic encephalopathy, showing hypermetabolism during the acute period 2-5 days after birth asphyxia (Blennow et al., 1995) and lower metabolism during the subacute

period (at the age of 4-24 days) after asphyxia (Thorngren-Jerneck et al., 2001).

severe HIE/poor prognosis by this time (Ilves et al., 2009a).

Such steady increase of the mean BFV is not found in infants with a severe HIE/poor prognosis during the first months after asphyxia (Figure 1). After the extremely high cerebral BFV during the first days of life significantly lower mean cerebral BFV develops during the first months after asphyxia in severe HIE infants. At the same age the enlargement of lateral ventricles, multicystic encephalopathy and the suboptimal head circumference develops in infants with a severe HIE / poor neurodevelopmental outcome suggesting decreased brain volume due to a massive loss of the brain tissue in infants with a

It is not known whether this decrease in the mean BFV in infants with a severe HIE/poor prognosis is caused only by the low brain volume or whether these infants have lower metabolism or because of both problems. Severe HIE infants had a low head circumference with wide liquor spaces and hence the low brain volume and therefore the required cerebral BFV to fulfil energy requirements for the damaged decreased cerebral parenchyma can be lower. Such decreased brain volume probably no longer needs a normal blood flow. It is also possible that the requirement for energetic fuel is low because of the low metabolism in

longer period after asphyxia.

**6.2 Long-term changes in Doppler sonography**

the damaged cells in the cases of severe brain damage. The only published case report, following longitudinal changes in cerebral metabolism in an infant with HIE and subsequent cerebral palsy, has demonstrated transient hypermetabolism in the neonatal period followed by severe hypometabolism later during childhood (Batista et al., 2007). More longitudinal data about cerebral blood flow and metabolism is needed to understand the causes of long term low cerebral blood flow velocities in infants with a severe HIE/poor prognosis months after birth asphyxia.

#### **6.3 US and Doppler findings in visceral organs**

Although the central nervous system is disturbed in 70% of infants after severe birth asphyxia (Martin-Ancel et al., 1995), up to 80-90% of infants develop disturbances in other organs (Martin-Ancel et al., 1995; Shah et al., 2004; Wayenberg et al., 1998). The interruption of the placental blood flow during labour and the decompensation of the circulatory responses lead to systemic hypotension and ischemia in different organs. Redistribution of the blood during asphyxia is the major protective mechanism in order to maintain the perfusion of vital organs such as the brain, heart and adrenal glands, but it causes ischemic damage to the visceral organs like kidneys and gut (Perlman, 2006; Stola & Perlman, 2008). Early BFV changes have been documented in critically ill infants following birth asphyxia in the cerebral (Bennhagen et al., 1998; Ilves, et al., 2009b), renal (RA) (Ilves et al., 2009b; Luciano et al., 1998), superior mesenteric arteries (SMA) (Ilves et al., 2009b; Koc et al., 1998) or in CA (Ilves et al., 2009b).

Different patterns of post-injury BFV changes exist in the visceral arteries compared to the cerebral arteries in asphyxiated infants with HIE. The mean BFV in the SMA and CA (but not in the RA) increased in the infants with mild-moderate HIE during the first 12 h after asphyxia (Ilves et al., 2009a, 2009b). The reperfusion of ischemic intestine and gastric mucosa is characterised by an initial hyperaemia with ensuing mucosal repair, as shown in animal models (Meleagros et al., 1994). The increase in BFV, seen in the SMA and CA but not in the RA during the first hours after asphyxia, can be the compensatory hyperaemia in the gastrointestinal tract, stomach and liver in the infants with mildmoderate HIE. Such differences in the compensatory capabilities in the RA, SMA and CA can explain the differences in the frequency of severe organ failure found in asphyxiated infants. Renal failure is found to develop more often in 40-57% of asphyxiated infants compared to a lower rate (30%) of gastrointestinal complications in asphyxiated term infants; liver failure is a rare complication in the infants with severe HIE (Martin-Ancel et al., 1995; Perlman et al., 1989).

The lack of hyperaemia in the SMA and CA and a decrease in BFV in the RA already during the first hours after asphyxia in severe HIE infants, despite vasoactive treatment and normal BP shows decreased compensatory capabilities in the infants with severe HIE to the restore blood flow in the visceral arteries. Extremely low BFV in all the visceral arteries was found during the first day in infants with a very long resuscitation period and the fatal outcome. These infants had normal blood pressure but a very high BFV in the cerebral arteries and a very low BFV in the visceral arteries already during the first day of life with the development of severe HIE, severe renal, gastrointestinal and hepatic failure as well as cardiac failure. Animal models have indicated that reperfusion is the main mechanism of injury after intestinal or renal ischemia; however, the post-ischemic

Sonographic Changes in Hypoxic-Ischaemic Encephalopathy 83

Sonography is an excellent tool in screening of asphyxiated infants with HIE and evaluating the prognosis of asphyxiated infants. Advances in the US equipment now permit the visualization of structures not previously shown. Despite some limitations, the US technique effectively depicts parenchymal abnormalities of the neonatal brain, showing good correlation with MRI findings. The parenchymal abnormalities depicted on US are not as florid or clearly visualized as on MRI and US might not depict as many focal lesions as MRI, especially those placed cortically. Therefore, US might severely underestimate the degree of injury, and the findings might indeed represent the tip of the iceberg. Despite this, US is a more effective modality in this group of patients than it has been suggested in the literature and remains an excellent screening modality for use in neonates too critically ill to be transported to MRI. MRI should ideally evaluate every infant with neonatal encephalopathy as early as possible, as the window required to demonstrate injury in DWI is small. However, high-quality US is very sensitive in detecting injuries and is often the only study available during the initial evaluation of these critcally ill patients or in those under hypothermic treatment. US provides an option for the interval follow-up assessment of these infants, even if the follow-up MRI is planned (Epelman et al., 2010). Differences exist in the blood flow velocity in the brain and in visceral organs in the infants with a different severity of HIE with a high cerebral blood flow and a low RI developing in the infants with a poor prognosis. In the infants with HIE treated with therapeutic hypothermia, the low resistance index is probably not as good a predictor of a poor outcome as in normothermia

Adriani, G., Persico, A., Tursini, S., Ballone, E., D Cirotti & Chiesa, PL. The renal-resistive

Agata, Y., Hiraishi, S., Misawa, H., Hirota, H., Nowatari, M., Hiura, K., Fujino, M., Oguchi,

Akinbi, H., Abbasi, S., Hilpert, PL. & Bhutni, VK. Gastrointestinal and renal blood flow velocity profile in neonates with birth asphyxia. *J Pediatr* 1994; 125: 625–627.

Archer, LN., Levene, MI. & Evans, DH. Cerebral artery Doppler ultrasonography for prediction of outcome after perinatal asphyxia. *Lancet* 1986; 2: 1116–1118. Ashwal, S., Majcher, JS., Vain, N., & Longo, LD. Patterns of fetal lamb regional cerebral blood flow during and after prolonged hypoxia. *Pediatr Res* 1980;14: 1104–1110. Babcock, DS. & Ball, W. Jr. Postasphyxial encephalopathy in full-term infants: US diagnosis.

Barkovich, AJ. 2005. Brain and spine injuries in infancy and childhood*.* In: *Barkovich AJ, ed.*

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Andreoli, SP. Acute renal failure in the newborn. *Semin Perinatol* 2004; 28: 112–123.

index from the last 3 months of pregnancy to 6 months old. *BJU International* 2001;

K. & Horiguchi, Y. Regional blood flow distribution and left ventricular output during early neonatal life: A quantitative ultrasonographic assessment. *Pediatr Res*

**8. Conclusions**

and further studies are needed in this area.

**9. References**

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4160-4918-0, Philadelphia.

reperfusion injury is related primarily to the magnitude and time of the total ischemia (Rangan & Bulkley, 1993).

In infants with severe HIE or poor outcome, a progressive decrease in the mean BFV was found in the RA and SMA, being the lowest during the second day of life (Akinbi et al., 1994; Ilves et al., 2009b; Luciano et al., 1998). A decrease in the renal blood flow during the first day of life carries a high risk of the development of acute renal failure (Akinbi et al., 1994; (Ilves et al., 2009b; Luciano et al., 1998). A number of animal studies have provided evidence that oxygen metabolites, different vasoconstrictive molecules and intravascular clotting may play a role in the microcirculation derangement in the delayed progressive postischemic reperfusion injury (Fellman & Raivio, 1997; Perlman, 2006). In normal infants, vasodilation secondary to the copious production of endothelium-derived nitric oxide (NO) is favoured, but endothelial cell injury could shift this balance in favour of endothelin (ET)- 1-mediated vasoconstriction and would limit NO production, leading to intestinal ischemia and the tissue injury as from humans with NEC (Nankervis et al., 2008). A hypoxic/ischemic insult with the resulting activation of the coagulation cascade also plays a role in renal hypoperfusion (Andreoli, 2004).

During the first day of life, pressure-passive BFV in the RA and SMA but not in the CA has been described earlier in healthy infants in the presence of open ductus arteriosus (Ilves et al., 2008). This may reflect the relatively good autoregulation of the blood flow in the CA in healthy and asphyxiated newborn infants with vasoactive treatment having a good effect; however, extra factors can redistribute the blood flow, sparing the blood flow to the CA and decreasing the blood to the SMA and RA.

Our findings indicate that differences exist in postasphyxic changes in BFV in the cerebral and visceral organs in different severities of HIE. Increased BFV develops in the SMA and CA in the infants with mild to moderate HIE early postinjury. A severe increase in BFV in the cerebral arteries, but a decrease in the renal and superior mesenteric arteries develops by the second day of life in a severe HIE infant, indicating that a therapeutic window exists for visceral damage. As in healthy infants, a relatively spared blood flow in the CA is found in asphyxiated newborn infants. No data exists how the BFV in visceral organs change during postasphyxial hypothermia.

#### **7. Outcome**

Outcomes of babies with HIE vary according to the severity of the injury. The children with mild HIE can be expected to recover and the children with the severe form either develop severe disability or die. Between 15% and 20% of infants suffering HIE die during the neonatal period, and an additional 25% develop permanent neurologic deficits (Vannucci & Perlman, 1997).  The patients with moderate injuries invariably can develop spastic diplegia or quadriplegia (often falling under the umbrella term cerebral palsy) (Barkovich, 2005).

The children with moderate encephalopathy have a less certain prognosis (Ilves et al., 2009a), however the majority of infants with moderate HIE have major and/or cognitive disability in a long-term follow-up if followed during adolescence (Lindström et al., 2008)

#### **8. Conclusions**

82 Miscellanea on Encephalopathies – A Second Look

reperfusion injury is related primarily to the magnitude and time of the total ischemia

In infants with severe HIE or poor outcome, a progressive decrease in the mean BFV was found in the RA and SMA, being the lowest during the second day of life (Akinbi et al., 1994; Ilves et al., 2009b; Luciano et al., 1998). A decrease in the renal blood flow during the first day of life carries a high risk of the development of acute renal failure (Akinbi et al., 1994; (Ilves et al., 2009b; Luciano et al., 1998). A number of animal studies have provided evidence that oxygen metabolites, different vasoconstrictive molecules and intravascular clotting may play a role in the microcirculation derangement in the delayed progressive postischemic reperfusion injury (Fellman & Raivio, 1997; Perlman, 2006). In normal infants, vasodilation secondary to the copious production of endothelium-derived nitric oxide (NO) is favoured, but endothelial cell injury could shift this balance in favour of endothelin (ET)- 1-mediated vasoconstriction and would limit NO production, leading to intestinal ischemia and the tissue injury as from humans with NEC (Nankervis et al., 2008). A hypoxic/ischemic insult with the resulting activation of the coagulation cascade also plays a

During the first day of life, pressure-passive BFV in the RA and SMA but not in the CA has been described earlier in healthy infants in the presence of open ductus arteriosus (Ilves et al., 2008). This may reflect the relatively good autoregulation of the blood flow in the CA in healthy and asphyxiated newborn infants with vasoactive treatment having a good effect; however, extra factors can redistribute the blood flow, sparing the blood flow to the CA and

Our findings indicate that differences exist in postasphyxic changes in BFV in the cerebral and visceral organs in different severities of HIE. Increased BFV develops in the SMA and CA in the infants with mild to moderate HIE early postinjury. A severe increase in BFV in the cerebral arteries, but a decrease in the renal and superior mesenteric arteries develops by the second day of life in a severe HIE infant, indicating that a therapeutic window exists for visceral damage. As in healthy infants, a relatively spared blood flow in the CA is found in asphyxiated newborn infants. No data exists how the BFV in visceral organs change during

Outcomes of babies with HIE vary according to the severity of the injury. The children with mild HIE can be expected to recover and the children with the severe form either develop severe disability or die. Between 15% and 20% of infants suffering HIE die during the neonatal period, and an additional 25% develop permanent neurologic deficits (Vannucci & Perlman, 1997).  The patients with moderate injuries invariably can develop spastic diplegia or quadriplegia (often falling under the umbrella term cerebral palsy) (Barkovich, 2005).

The children with moderate encephalopathy have a less certain prognosis (Ilves et al., 2009a), however the majority of infants with moderate HIE have major and/or cognitive disability in a long-term follow-up if followed during adolescence (Lindström et al., 2008)

(Rangan & Bulkley, 1993).

role in renal hypoperfusion (Andreoli, 2004).

decreasing the blood to the SMA and RA.

postasphyxial hypothermia.

**7. Outcome**

Sonography is an excellent tool in screening of asphyxiated infants with HIE and evaluating the prognosis of asphyxiated infants. Advances in the US equipment now permit the visualization of structures not previously shown. Despite some limitations, the US technique effectively depicts parenchymal abnormalities of the neonatal brain, showing good correlation with MRI findings. The parenchymal abnormalities depicted on US are not as florid or clearly visualized as on MRI and US might not depict as many focal lesions as MRI, especially those placed cortically. Therefore, US might severely underestimate the degree of injury, and the findings might indeed represent the tip of the iceberg. Despite this, US is a more effective modality in this group of patients than it has been suggested in the literature and remains an excellent screening modality for use in neonates too critically ill to be transported to MRI. MRI should ideally evaluate every infant with neonatal encephalopathy as early as possible, as the window required to demonstrate injury in DWI is small. However, high-quality US is very sensitive in detecting injuries and is often the only study available during the initial evaluation of these critcally ill patients or in those under hypothermic treatment. US provides an option for the interval follow-up assessment of these infants, even if the follow-up MRI is planned (Epelman et al., 2010). Differences exist in the blood flow velocity in the brain and in visceral organs in the infants with a different severity of HIE with a high cerebral blood flow and a low RI developing in the infants with a poor prognosis. In the infants with HIE treated with therapeutic hypothermia, the low resistance index is probably not as good a predictor of a poor outcome as in normothermia and further studies are needed in this area.

#### **9. References**

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**5**

*Belgium*

**Neoplasm Related Encephalopathies**

*1 Department of Medical Oncology,*

*2Department of Neurology, Ghent University Hospital*

Lore Lapeire1, Anne Sieben2, Patrick Santens2 and Simon Van Belle1

Encephalopathy is a common clinical syndrome in cancer patients. The underlying causes of cancer related encephalopathies are various and mostly non-specific, such as metabolic disturbances as seen in critically ill patients. Electrolyte disturbances, hypoxia, hyperammonemia, thiamine deficiency and toxic reactions are all possible causes of encephalopathy in cancer patients. Structural lesions such as brain metastasis or venous thrombosis can evoke intracranial hypertension, also inducing a clinical picture resembling

However, next to these non-specific causes of cancer related encephalopathy, there are also uncommon but highly specific encephalopathic syndromes related to malignancies and their treatments. In this chapter, we discuss encephalopathy associated with these uncommon

Paraneoplastic neurological syndromes (PNS) are clinical syndromes caused by nonmetastatic manifestations of neoplasm outside the nervous system. PNS can be immunemediated, and in those cases an association with circulating anti-neuronal antibodies and

In non-immune mediated PNS, encephalopathy can be induced by tumour products such as hypertensive encephalopathy in patients with aldosterone-producing adenoma. Encephalopathy can also be the result of a depletion of substrate by direct competition

In addition to these paraneoplastic neurological syndromes, we will present two typical cancer treatment related neurological conditions causing encephalopathy: PRES (posterior reversible

Pathophysiological mechanisms will be discussed, as well as associated clinical symptoms,

PNS are unusual presentations of cancer, occurring in 1 per 10 000 patients with malignancies. Clinically well defined immune-mediated PNS account for 10% of all non-

between the central nervous tissue and the tumour, e.g. carcinoid encephalopathy.

encephalopathy syndrome) and PML (progressive multifocal leukoencephalopathy).

cytotoxic T-cells, in combination with specific tumours, can be made.

**1. Introduction**

encephalopathy.

clinical syndromes.

prognosis and possible treatments.

**2. Paraneoplastic neurological syndromes**

Yoxall, CW. & Weindling, AM. Measurement of cerebral oxygen consumption in the human neonate using near infrared spectroscopy: cerebral oxygen consumption increases with advancing gestational age. *Pediatr Res* 1998; 44: 283–290.

### **Neoplasm Related Encephalopathies**

Lore Lapeire1, Anne Sieben2, Patrick Santens2 and Simon Van Belle1

*1 Department of Medical Oncology, 2Department of Neurology, Ghent University Hospital Belgium*

#### **1. Introduction**

90 Miscellanea on Encephalopathies – A Second Look

Yoxall, CW. & Weindling, AM. Measurement of cerebral oxygen consumption in the human

with advancing gestational age. *Pediatr Res* 1998; 44: 283–290.

neonate using near infrared spectroscopy: cerebral oxygen consumption increases

Encephalopathy is a common clinical syndrome in cancer patients. The underlying causes of cancer related encephalopathies are various and mostly non-specific, such as metabolic disturbances as seen in critically ill patients. Electrolyte disturbances, hypoxia, hyperammonemia, thiamine deficiency and toxic reactions are all possible causes of encephalopathy in cancer patients. Structural lesions such as brain metastasis or venous thrombosis can evoke intracranial hypertension, also inducing a clinical picture resembling encephalopathy.

However, next to these non-specific causes of cancer related encephalopathy, there are also uncommon but highly specific encephalopathic syndromes related to malignancies and their treatments. In this chapter, we discuss encephalopathy associated with these uncommon clinical syndromes.

Paraneoplastic neurological syndromes (PNS) are clinical syndromes caused by nonmetastatic manifestations of neoplasm outside the nervous system. PNS can be immunemediated, and in those cases an association with circulating anti-neuronal antibodies and cytotoxic T-cells, in combination with specific tumours, can be made.

In non-immune mediated PNS, encephalopathy can be induced by tumour products such as hypertensive encephalopathy in patients with aldosterone-producing adenoma. Encephalopathy can also be the result of a depletion of substrate by direct competition between the central nervous tissue and the tumour, e.g. carcinoid encephalopathy.

In addition to these paraneoplastic neurological syndromes, we will present two typical cancer treatment related neurological conditions causing encephalopathy: PRES (posterior reversible encephalopathy syndrome) and PML (progressive multifocal leukoencephalopathy).

Pathophysiological mechanisms will be discussed, as well as associated clinical symptoms, prognosis and possible treatments.

#### **2. Paraneoplastic neurological syndromes**

PNS are unusual presentations of cancer, occurring in 1 per 10 000 patients with malignancies. Clinically well defined immune-mediated PNS account for 10% of all non-

Neoplasm Related Encephalopathies 93

The more common PNS are syndromes of the peripheral nervous system and neuromuscular junction: Lambert-Eaton myasthenic syndrome (LEMS) which affects 3% of patients with SCLC and myasthenia gravis, occurring in 15% of patients with thymoma.

Paraneoplastic encephalomyelitis is the PNS of the central nervous system most frequently

Tumours which are commonly involved in PNS of the central nervous system express neuroendocrine proteins (e.g. small-cell lung cancer (SCLC)), affect organs with immunoregulatory

Tumours originating from tissue producing immunoglobulins (e.g. lymphomas) are more commonly involved in PNS of the peripheral nervous system (Dalmau & Rosenfield, 2008). As mentioned above, circulating antibodies against the expressed tumoural proteins can be associated with PNS. Different antibodies can be associated with the same PNS and inversely, the same antibody can be associated with different clinical syndromes (Voltz, 2002). Moreover, several PNS may co-occur in the same patient, particularly if the

The detection of antibodies in serum or cerebrospinal fluid confirms the clinical diagnosis of a paraneoplastic syndrome and allows early identification of an underlying tumour. However, the failure of finding antibodies does not exclude a diagnosis of PNS and inversely, antibodies have been detected in patients without PNS, e.g. anti-Hu antibodies (in low titres) in patients with SCLC can be present without any neurological symptoms (Nath

Next to immune mediated PNS, there are also non-immunologic mechanisms that can be involved in PNS. Cytokines and hormones produced by tumours can induce an encephalopathy. Another yet uncommon cause of encephalopathy involves the competition between the tumour and nervous tissue for a specific substrate, e.g. carcinoid tumours and tryptophan. This very rare and particular picture will be described further in this chapter.

The identification in 1985 of anti-neuronal antibodies in the serum of patients with nonmetastatic neurological complications of cancer, led to the hypothesis that paraneoplastic neurological syndromes are immune-mediated (Voltz, 2002). Antibodies against neuronal

The central and peripheral nervous system are considered to be low immunogenetic systems, since the presence of the blood/brain barrier means that antigens which are localised in the cerebrospinal fluid do not normally induce an immune response. Aberrant expression of neuronal antigens by a tumour outside this barrier, can lead to an immunological response which breaches the blood/brain barrier, as such inducing a

Before a disorder can be considered to be antibody mediated, several criteria have to be

1. The reactivity of the antibody with the antigen results in antigen loss and/or neuronal

**2.1 Pathogenetic mechanism of immune-mediated PNS**

possible influence on the central and peripheral nervous system.

fulfilled (Koch's postulates, as cited in Sutton & Winer, 2002):

loss, inducing the clinical phenotype.

antigens have since then been extensively described.

proteins (e.g. thymoma) or contain mature or immature neuronal tissue (e.g. teratoma).

seen.

underlying tumour is SCLC.

& Grant, 1997).

metastatic neurological complications with cancer. However, the percentage of patients with malignancies presenting with peripheral neuropathy or muscle weakness is much higher.

About 3-5% of patients with small-cell lung cancer (SCLC), 15-20% of patients with thymoma and about 10% of patients with plasma-cell dyscrasias develop PNS. In patients with cancer of the breast or ovary, prevalence is well below 1% (Darnell & Posner, 2003).

In 2/3 of patients, PNS will precede the diagnosis of malignancy. Identification of the PNS may allow tumour diagnosis when the tumour is small, localised and more responsive to treatment. Therefore, it is very important to recognize PNS with their various clinical presentations and subsequently start screening for malignancy when PNS is suspected.

Clinical presentations of PNS are various and include peripheral symptoms as well as central signs (Table 1). Peripheral symptomatology includes neuropathy, myasthenia and muscle weakness, whereas central signs are heterogeneous and include ataxia, visual disturbances, epilepsy, dysphagia and changes in mental state.

#### **PARANEOPLASTIC SYNDROMES OF THE NERVOUS SYSTEM**

Paraneoplastic syndromes of the central nervous system

Paraneoplastic syndromes of the peripheral nervous system

Paraneoplastic syndromes of the neuromuscular junction and muscle

Table 1. Immune Mediated Paraneoplastic Syndromes of the Nervous System (Dalmau et al., 2007)

metastatic neurological complications with cancer. However, the percentage of patients with malignancies presenting with peripheral neuropathy or muscle weakness is much higher. About 3-5% of patients with small-cell lung cancer (SCLC), 15-20% of patients with thymoma and about 10% of patients with plasma-cell dyscrasias develop PNS. In patients with cancer of the breast or ovary, prevalence is well below 1% (Darnell & Posner, 2003).

In 2/3 of patients, PNS will precede the diagnosis of malignancy. Identification of the PNS may allow tumour diagnosis when the tumour is small, localised and more responsive to treatment. Therefore, it is very important to recognize PNS with their various clinical presentations and subsequently start screening for malignancy when PNS is suspected.

Clinical presentations of PNS are various and include peripheral symptoms as well as central signs (Table 1). Peripheral symptomatology includes neuropathy, myasthenia and muscle weakness, whereas central signs are heterogeneous and include ataxia, visual

Paraneoplastic encephalomyelitis (limbic encephalitis, brainstem encephalitis,

disturbances, epilepsy, dysphagia and changes in mental state.

Paraneoplastic syndromes of the central nervous system Paraneoplastic cerebellar degeneration

Paraneoplastic opsoclonus-myoclonus-ataxia

Paraneoplastic syndromes of the peripheral nervous system

 Paraneoplastic Stiff-man syndrome Paraneoplastic necrotizing myelopathy

Subacute sensory neuronopathy

Acute sensorimotor neuropathy

Chronic sensorimotor neuropathy

 Lambert-Eaton myasthenic syndrome Polymyositis/Dermatomyositis Acute necrotizing myopathy

Carcinomatous neuromyopathy

Polyradiculoneuropathy (Guillain-Barré)

myelitis)

Paraneoplastic chorea

Autonomic neuropathy

 Vasculitic neuropathy Neuromyotonia

Cachectic myopathy

Carcinoid myopathy

al., 2007)

Brachial neuritis

**PARANEOPLASTIC SYNDROMES OF THE NERVOUS SYSTEM**

Motor neuron syndromes (ALS; subacute motor neuronopathy)

Sensorimotor neuropathies associated with plasma cell dyscrasias

Table 1. Immune Mediated Paraneoplastic Syndromes of the Nervous System (Dalmau et

Paraneoplastic syndromes of the neuromuscular junction and muscle

The more common PNS are syndromes of the peripheral nervous system and neuromuscular junction: Lambert-Eaton myasthenic syndrome (LEMS) which affects 3% of patients with SCLC and myasthenia gravis, occurring in 15% of patients with thymoma.

Paraneoplastic encephalomyelitis is the PNS of the central nervous system most frequently seen.

Tumours which are commonly involved in PNS of the central nervous system express neuroendocrine proteins (e.g. small-cell lung cancer (SCLC)), affect organs with immunoregulatory proteins (e.g. thymoma) or contain mature or immature neuronal tissue (e.g. teratoma).

Tumours originating from tissue producing immunoglobulins (e.g. lymphomas) are more commonly involved in PNS of the peripheral nervous system (Dalmau & Rosenfield, 2008).

As mentioned above, circulating antibodies against the expressed tumoural proteins can be associated with PNS. Different antibodies can be associated with the same PNS and inversely, the same antibody can be associated with different clinical syndromes (Voltz, 2002). Moreover, several PNS may co-occur in the same patient, particularly if the underlying tumour is SCLC.

The detection of antibodies in serum or cerebrospinal fluid confirms the clinical diagnosis of a paraneoplastic syndrome and allows early identification of an underlying tumour. However, the failure of finding antibodies does not exclude a diagnosis of PNS and inversely, antibodies have been detected in patients without PNS, e.g. anti-Hu antibodies (in low titres) in patients with SCLC can be present without any neurological symptoms (Nath & Grant, 1997).

Next to immune mediated PNS, there are also non-immunologic mechanisms that can be involved in PNS. Cytokines and hormones produced by tumours can induce an encephalopathy. Another yet uncommon cause of encephalopathy involves the competition between the tumour and nervous tissue for a specific substrate, e.g. carcinoid tumours and tryptophan. This very rare and particular picture will be described further in this chapter.

#### **2.1 Pathogenetic mechanism of immune-mediated PNS**

The identification in 1985 of anti-neuronal antibodies in the serum of patients with nonmetastatic neurological complications of cancer, led to the hypothesis that paraneoplastic neurological syndromes are immune-mediated (Voltz, 2002). Antibodies against neuronal antigens have since then been extensively described.

The central and peripheral nervous system are considered to be low immunogenetic systems, since the presence of the blood/brain barrier means that antigens which are localised in the cerebrospinal fluid do not normally induce an immune response. Aberrant expression of neuronal antigens by a tumour outside this barrier, can lead to an immunological response which breaches the blood/brain barrier, as such inducing a possible influence on the central and peripheral nervous system.

Before a disorder can be considered to be antibody mediated, several criteria have to be fulfilled (Koch's postulates, as cited in Sutton & Winer, 2002):

1. The reactivity of the antibody with the antigen results in antigen loss and/or neuronal loss, inducing the clinical phenotype.

 Well characterized onconeural antibodies (APCA: anti-Purkinje cell antibody, ANNA: anti-neuronal nuclear antibody, CRMP: collapsin response mediator proteins,

Anti-NMDAR Encephalitis Ovarian teratoma

Table 3. Antibodies that occur with and without malignancy (NMDA: N-methyl-D-Asparginic acid receptor, VGKC: voltage-gated potassium channel, VGCC: voltage-gated calcium channel, AchR: acetylcholine receptor, nAchR: neuronal acetylcholine receptor, GAD: glutaminic acid

Anti-AchR Myasthenia Gravis Thymoma Anti-nAchR Subacute pandysautonomia SCLC, other

decarboxylase, LEMS: Lambert-Eaton myastenic syndrome) (Dalmau et al., 2007)

Anti-Yo (APCA1) Paraneoplastic cerebellar degeneration

Encephalomyelitis Autonomic dysfunction

Limbic encephalitis

Limbic encephalitis

Anti-Ma (1&2) Limbic/mesodiencephalic/ hypothalamic

Stiff-person syndrome Encephalomyelitis

mGluR: metabotropic glutamate receptor) (Dalmau et al., 2007)

neuromyotonia

cerebellar ataxia limbic encephalitis

**Antibody Paraneoplastic neurological syndrome**

other

PCD

other

Anti-GAD Stiff-person syndrome

Anti-VGKC Limbic encephalitis

Anti-VGCC LEMS

Anti-ANNA3 Various PNS of the CNS SCLC Anti-PCA2 Various PNS of the CNS SCLC Anti-Zic PCD SCLC

Sensory neuronopathy Sensorimotor neuropathy Encephalomyelitis

Subacute sensory neuronopathy

(PCD)

PCD

Chorea

PCD

Anti-Ri (ANNA2) Brainstem encephalitis

PCD

encephalitis

Anti-Hu (ANNA1)

Anti-CV2 (CRMP5)

Anti-

amphiphysin

In the group of onconeural antibodies, only the antibodies reacting against VGCC (voltagegated calcium channel) and mGluR1 (metabotropic glutamate receptor) have met the above mentioned criteria and can be considered to be pathogenic antibodies, e.g. anti-VGCC antibodies inducing the Lambert-Eaton Myasthenic Syndrome. However, the anti-VGCC antibodies found in paraneoplastic cerebellar degeneration are not found to be pathogenic, whereas anti-GluR1 antibodies are the cause of the cerebellar degeneration in patients with Hodgkin's disease (Sutton & Winer, 2002).

Anti-VGCC antibodies and anti-GluR1 antibodies are antibodies reactive to antigens on the cell surface of neurones. Up till now, none of the antibodies acting against an intracellular neuronal antigen are found to be pathogenic.

In post-mortem findings of patients with PNS and antibodies against intracellular targets, the finding of infiltration of T-cells in the affected central nervous tissue has opened the possible role of a cytotoxic T-cell mediated immune response.

This pathway includes T-cell immune responses that probably act against the target antigens of the circulating antibodies. E.g. Hu antigen-specific T-cells have been identified in blood and cerebrospinal fluid of patients with circulating anti-Hu antibodies. Support for this additional T-cell mediated mechanism includes the difficulties in treating these disorders with strategies directed at the humoral immune response (Dalmau & Rosenfield, 2008).

This pathogenesis has been confirmed in the development of paraneoplastic encephalomyelitis in patients with SCLC and a positive anti-Hu antibody serology.

It remains to be investigated whether cytotoxic T-lymphocytes against the Yo-antigen are responsible for the paraneoplastic cerebellar degeneration (Sutton & Winer, 2002).

Thus, antibodies seem to be in most cases a marginal phenomenon opposed to a causing factor. The importance of detecting the antibody remains however essential, as screening for malignancies can be specified and the prognosis of the PNS can be formulated.

#### **2.2 Antineuronal antibodies**

Antineuronal antibodies belong to a group of heterogeneous antibodies, which tend to present a diversity of clinical symptoms.

Two groups can be separated: antineuronal antibodies formed in the presence of a malignancy, i.e. paraneoplastic or onconeural antibodies (table 2), while the other group is often but not always associated with neoplasm (table 3).

The majority of antibodies can be detected using indirect immunofluorescence. A confirmation test using Western blot against recombinant antigen is an additional value (Sutton & Winer, 2002).

2. A passive transfer of the immunoglobulins of an affected patient to an animal should

3. Immunotherapy that leads to a reduction of antibody titres should be associated with

4. Immunization of an animal with the purified antigen leads to the development of an

In the group of onconeural antibodies, only the antibodies reacting against VGCC (voltagegated calcium channel) and mGluR1 (metabotropic glutamate receptor) have met the above mentioned criteria and can be considered to be pathogenic antibodies, e.g. anti-VGCC antibodies inducing the Lambert-Eaton Myasthenic Syndrome. However, the anti-VGCC antibodies found in paraneoplastic cerebellar degeneration are not found to be pathogenic, whereas anti-GluR1 antibodies are the cause of the cerebellar degeneration in patients with

Anti-VGCC antibodies and anti-GluR1 antibodies are antibodies reactive to antigens on the cell surface of neurones. Up till now, none of the antibodies acting against an intracellular

In post-mortem findings of patients with PNS and antibodies against intracellular targets, the finding of infiltration of T-cells in the affected central nervous tissue has opened the

This pathway includes T-cell immune responses that probably act against the target antigens of the circulating antibodies. E.g. Hu antigen-specific T-cells have been identified in blood and cerebrospinal fluid of patients with circulating anti-Hu antibodies. Support for this additional T-cell mediated mechanism includes the difficulties in treating these disorders with strategies directed at the humoral immune response (Dalmau & Rosenfield, 2008).

This pathogenesis has been confirmed in the development of paraneoplastic

It remains to be investigated whether cytotoxic T-lymphocytes against the Yo-antigen are

Thus, antibodies seem to be in most cases a marginal phenomenon opposed to a causing factor. The importance of detecting the antibody remains however essential, as screening for

Antineuronal antibodies belong to a group of heterogeneous antibodies, which tend to

Two groups can be separated: antineuronal antibodies formed in the presence of a malignancy, i.e. paraneoplastic or onconeural antibodies (table 2), while the other group is

The majority of antibodies can be detected using indirect immunofluorescence. A confirmation test using Western blot against recombinant antigen is an additional value

encephalomyelitis in patients with SCLC and a positive anti-Hu antibody serology.

responsible for the paraneoplastic cerebellar degeneration (Sutton & Winer, 2002).

malignancies can be specified and the prognosis of the PNS can be formulated.

clinical improvement or at least stabilisation of the symptomatology.

antibody response, resulting in the clinical phenotype.

possible role of a cytotoxic T-cell mediated immune response.

induce the clinical phenotype.

Hodgkin's disease (Sutton & Winer, 2002).

neuronal antigen are found to be pathogenic.

**2.2 Antineuronal antibodies**

(Sutton & Winer, 2002).

present a diversity of clinical symptoms.

often but not always associated with neoplasm (table 3).

Table 2. Well characterized onconeural antibodies (APCA: anti-Purkinje cell antibody, ANNA: anti-neuronal nuclear antibody, CRMP: collapsin response mediator proteins, mGluR: metabotropic glutamate receptor) (Dalmau et al., 2007)

Table 3. Antibodies that occur with and without malignancy (NMDA: N-methyl-D-Asparginic acid receptor, VGKC: voltage-gated potassium channel, VGCC: voltage-gated calcium channel, AchR: acetylcholine receptor, nAchR: neuronal acetylcholine receptor, GAD: glutaminic acid decarboxylase, LEMS: Lambert-Eaton myastenic syndrome) (Dalmau et al., 2007)

Neoplasm Related Encephalopathies 97

Anti-Hu antibody reacts with a neuronal nuclear antigen that belongs to a family of RNA

There are 4 antigens which are recognized by anti-Hu antibodies: HuD, HuC, HuR and Hel-N1. HuD, HuC and Hel-N1 are expressed in terminally differentiated neurons, whereas HuR is expressed in all proliferating cells (Sutton & Winer, 2002). HuD, HuC and Hel-N1

Patients with paraneoplastic syndromes and anti-Hu antibodies may develop concurrent antibodies to other onconeural antigens. They include anti-CV2 (CRMP5), anti-

Immunocytochemistry of serum or CSF shows an anti-neuronal nuclear antibody which is identical to the ANNA-1 antibody on immunocytochemical criteria. With western blotting, a

This antibody has mostly been described in patients with opsoclonus-myoclonus-ataxia with SCLC as underlying tumour. Associated PNS can be paraneoplastic cerebellar degeneration

Next to SLCL, other underlying neoplasms can be malignancies of breast, ovary and bladder

The antigen recognized by anti-Ri antibodies is a protein belonging to a family of RNAbinding proteins, mainly expressed in the nervous system. There are 2 Ri-antigens: Nova-1

Recent pathological and functional MRI findings suggest that the disinhibition of the fastigial nucleus of the cerebellum is involved, causing the clinical picture. However, it remains unclear why this structure is most susceptible to the toxicity of the anti-Ri antibody, whilst the inflammatory process is seen in the entire central nervous system (Dalmau &

Patients can manifest with different clinical syndromes. Sensorimotor neuropathy and paraneoplastic cerebellar degeneration are most commonly found. Less frequent are limbic

amphiphysin, anti-Ri, anti-VGCC and anti-Zic4 antibodies.

(Darnell & Posner, 2003; Gozzard & Maddison, 2010).

**2.2.4 Anti-CV2 antibodies (=Anti-CRMP5 antibodies)**

Rosenfield, 2008; Sutton & Winer, 2002).

encephalitis, encephalomyelitis and LEMS.

and Nova-2, widely expressed within the central nervous system.

**2.2.3 Anti-Ri antibody (ANNA-2 = anti-neuronal nuclear antibody type 2)**

different banding pattern can be seen, distinguishing this antibody from ANNA-1.

Antigen

binding proteins.

are expressed by all SCLC's. Immunologic associations

Clinical associations

Tumour associations

Clinical associations

Antigen

(Gozzard & Maddison, 2010).

#### **2.2.1 Anti-Yo antibody (APCA-1 = anti-Purkinje cell antibody type 1)**

#### Clinical associations

Anti-Yo antibodies are mostly clinically accompanied by a paraneoplastic cerebellar degeneration (>50%).

#### Tumour associations

Most patients are women and associated tumours are almost exclusively gynaecologic (47% ovarian, 13% endometrial and tubal carcinoma) or breast cancers (25%). Some patients with SCLC, various adenocarcinomas, transitional cell carcinoma of the bladder or lymphoma have been described (Gozzard & Maddison, 2010).

#### Antigen

The Yo-antigens belong to a family of DNA binding proteins. The expression of the antigens is limited to the cytoplasm of Purkinje cells. Anti-Yo antibodies recognize 2 antigens: a cytoplasmatic protein called CDR62 (cerebellar degeneration-related 62kDa protein) and a minor cytoplasmatic protein of 34 kDa, named CDR34.

Three genes have been cloned (cdr 1-3). Cdr1 encodes the 34 kDa protein while Cdr2 encodes the CDR62 protein that specifically binds to c-Myc thereby downregulating its activity. Disruption of this interaction by anti-Yo antibodies may increase c-Myc activity, leading to apoptosis of Purkinje cells (Dalmau & Rosenfield, 2008; Nath & Grant, 1997; Voltz, 2002).

However, different studies have demonstrated T-lymphocytes in the leptomeninges, brain stem and medulla, without lymphocytic infiltration or signs of inflammation in the cerebellar cortex in patients with a later stage of the cerebellar degeneration (Sutton & Winer, 2002). It is proposed that the loss of the Purkinje cells represent a final "burn out" stage of a cell-mediated immune process (Voltz, 2002). This hypothesis is supported by the presence of T-lymphocytes in the cerebellar cortex of a patient, who died 4 months after onset of the cerebellar symptomatology (Sutton & Winer, 2002).

#### **2.2.2 Anti-Hu antibody (ANNA-1 = anti- neuronal nuclear antibody type 1)**

Clinical associations

As anti-Hu antibodies react with antigens localized in the nucleus of every neuronal cell, anti-Hu antibodies can cause a variety of PNS of the central and peripheral nerve tissue (table 2): paraneoplastic limbic encephalitis, paraneoplastic cerebellar degeneration, paraneoplastic encephalomyelitis and subacute sensory neuronopathy.

Identification of anti-Hu antibodies at a concentration greater than 1/500 in cerebrospinal fluid is highly sensitive for a PNS of the central nervous system, typically limbic encephalitis or paraneoplastic encephalomyelitis.

#### Tumour associations

80%-93% of patients with anti-Hu antibodies will have SCLC (Gozzard & Maddison, 2010); Nath & Grant, 1997). Extrathoracic tumours in association with anti-Hu antibodies include neuroblastoma (50%) and prostate cancer (Titulaer et al, 2011).

#### Antigen

96 Miscellanea on Encephalopathies – A Second Look

Anti-Yo antibodies are mostly clinically accompanied by a paraneoplastic cerebellar

Most patients are women and associated tumours are almost exclusively gynaecologic (47% ovarian, 13% endometrial and tubal carcinoma) or breast cancers (25%). Some patients with SCLC, various adenocarcinomas, transitional cell carcinoma of the bladder or lymphoma

The Yo-antigens belong to a family of DNA binding proteins. The expression of the antigens is limited to the cytoplasm of Purkinje cells. Anti-Yo antibodies recognize 2 antigens: a cytoplasmatic protein called CDR62 (cerebellar degeneration-related 62kDa protein) and a

Three genes have been cloned (cdr 1-3). Cdr1 encodes the 34 kDa protein while Cdr2 encodes the CDR62 protein that specifically binds to c-Myc thereby downregulating its activity. Disruption of this interaction by anti-Yo antibodies may increase c-Myc activity, leading to apoptosis of Purkinje cells (Dalmau & Rosenfield, 2008; Nath & Grant, 1997;

However, different studies have demonstrated T-lymphocytes in the leptomeninges, brain stem and medulla, without lymphocytic infiltration or signs of inflammation in the cerebellar cortex in patients with a later stage of the cerebellar degeneration (Sutton & Winer, 2002). It is proposed that the loss of the Purkinje cells represent a final "burn out" stage of a cell-mediated immune process (Voltz, 2002). This hypothesis is supported by the presence of T-lymphocytes in the cerebellar cortex of a patient, who died 4 months after

As anti-Hu antibodies react with antigens localized in the nucleus of every neuronal cell, anti-Hu antibodies can cause a variety of PNS of the central and peripheral nerve tissue (table 2): paraneoplastic limbic encephalitis, paraneoplastic cerebellar degeneration,

Identification of anti-Hu antibodies at a concentration greater than 1/500 in cerebrospinal fluid is highly sensitive for a PNS of the central nervous system, typically limbic encephalitis

80%-93% of patients with anti-Hu antibodies will have SCLC (Gozzard & Maddison, 2010); Nath & Grant, 1997). Extrathoracic tumours in association with anti-Hu antibodies include

**2.2.1 Anti-Yo antibody (APCA-1 = anti-Purkinje cell antibody type 1)**

have been described (Gozzard & Maddison, 2010).

minor cytoplasmatic protein of 34 kDa, named CDR34.

onset of the cerebellar symptomatology (Sutton & Winer, 2002).

**2.2.2 Anti-Hu antibody (ANNA-1 = anti- neuronal nuclear antibody type 1)**

paraneoplastic encephalomyelitis and subacute sensory neuronopathy.

neuroblastoma (50%) and prostate cancer (Titulaer et al, 2011).

Clinical associations

degeneration (>50%). Tumour associations

Antigen

Voltz, 2002).

Clinical associations

Tumour associations

or paraneoplastic encephalomyelitis.

Anti-Hu antibody reacts with a neuronal nuclear antigen that belongs to a family of RNA binding proteins.

There are 4 antigens which are recognized by anti-Hu antibodies: HuD, HuC, HuR and Hel-N1. HuD, HuC and Hel-N1 are expressed in terminally differentiated neurons, whereas HuR is expressed in all proliferating cells (Sutton & Winer, 2002). HuD, HuC and Hel-N1 are expressed by all SCLC's.

Immunologic associations

Patients with paraneoplastic syndromes and anti-Hu antibodies may develop concurrent antibodies to other onconeural antigens. They include anti-CV2 (CRMP5), antiamphiphysin, anti-Ri, anti-VGCC and anti-Zic4 antibodies.

#### **2.2.3 Anti-Ri antibody (ANNA-2 = anti-neuronal nuclear antibody type 2)**

Immunocytochemistry of serum or CSF shows an anti-neuronal nuclear antibody which is identical to the ANNA-1 antibody on immunocytochemical criteria. With western blotting, a different banding pattern can be seen, distinguishing this antibody from ANNA-1.

Clinical associations

This antibody has mostly been described in patients with opsoclonus-myoclonus-ataxia with SCLC as underlying tumour. Associated PNS can be paraneoplastic cerebellar degeneration (Gozzard & Maddison, 2010).

#### Tumour associations

Next to SLCL, other underlying neoplasms can be malignancies of breast, ovary and bladder (Darnell & Posner, 2003; Gozzard & Maddison, 2010).

Antigen

The antigen recognized by anti-Ri antibodies is a protein belonging to a family of RNAbinding proteins, mainly expressed in the nervous system. There are 2 Ri-antigens: Nova-1 and Nova-2, widely expressed within the central nervous system.

Recent pathological and functional MRI findings suggest that the disinhibition of the fastigial nucleus of the cerebellum is involved, causing the clinical picture. However, it remains unclear why this structure is most susceptible to the toxicity of the anti-Ri antibody, whilst the inflammatory process is seen in the entire central nervous system (Dalmau & Rosenfield, 2008; Sutton & Winer, 2002).

#### **2.2.4 Anti-CV2 antibodies (=Anti-CRMP5 antibodies)**

Clinical associations

Patients can manifest with different clinical syndromes. Sensorimotor neuropathy and paraneoplastic cerebellar degeneration are most commonly found. Less frequent are limbic encephalitis, encephalomyelitis and LEMS.

Neoplasm Related Encephalopathies 99

These antibodies are found in young women with a teratoma of the ovary. Clinically, patients present with a limbic encephalitis in combination with psychiatric symptoms and autonomic dysfunction. The neurological symptomatology can reverse after treatment of the

This antibody has a low frequency. A variety of neurological symptoms can occur, with cerebellar ataxia due to paraneoplastic cerebellar degeneration most frequently seen.

This metabotropic glutamate receptor antibody reacts with the mGluR1 receptor on the surface of Purkinje cells. There is an association with Hodgkin's lymphoma. Clinical

Patients with a positive serology for this antibody present typically with neuromyotonia. A PNS of the central nervous system occasionally seen is limbic encephalitis, commonly evolving to a less focalized encephalitis. Underlying tumours are SCLC and thymoma

This antibody has a well known association with Stiff-Person Syndrome. Recently patients with paraneoplastic cerebellar degeneration or limbic encephalitis were described. This antibody is frequently found in patients with insulin-dependent diabetes mellitus. When a

As 2/3 of PNS precede the diagnosis of malignancy, it is important to recognize the clinical

Several features are shared by most PNS of the CNS. The clinical presentation is a fast accumulation of symptoms of central nervous system involvement, evolving over weeks

MRI findings are non-specific and can show normal findings, relative atrophy of specific regions (e.g. cerebellum) or regional Gadolinium-enhancing lesions. In cerebrospinal fluid, mostly signs of inflammation or immune-mediated mechanisms are withheld: moderate lymphocytic pleocytosis (30-40 white blood cells/mm3), increased protein concentration (50-100 mg/dl), high IgG index and CSF-specific oligoclonal bands (Darnell

Because of the low prevalence of PNS, the PNS Euronetwork published diagnostic criteria

paraneoplastic mechanism is suspected, patients should be screened for a thymoma.

**2.3 Immune-mediated paraneoplastic syndromes of the central nervous system**

presentation is a cerebellar syndrome (Darnell & Posner, 2003).

Anti-VGKC antibodies (anti-voltage gated potassium channel antibodies)

Anti-GAD antibodies (anti-glutaminic acid decarboxylase antibodies)

picture and to start an appropriate screening for neoplasm.

for PNS (table 4) (PNS Euronetwork, 2002; Titulaer et al, 2011).

and severely disabling the patient.

& Posner, 2003).

Anti-NMDAR antibodies (anti-N-Methyl-D-Asparginic acid receptor antibodies)

tumour, as well as after immunotherapy.

Anti-Zic antibodies

(Titulaer et al, 2011).

Underlying tumour is SCLC.

Anti-mGluR1 receptor antibodies

#### Tumour associations

The tumour most commonly found in patients with anti-CV2 antibodies, is SCLC (60%- 77%). Further, thymoma (7%) and neoplasm of the uterus need to be excluded (Voltz, 2002).

#### Antigen

The target of anti-CV2 antibodies is a family of ~66 kDa proteins that are mainly expressed in the nervous system called CRMP for Collapsin Response Mediator Proteins. In the adult brain, the expression of CRMPs is dramatically down-regulated. However, they remain expressed in structures that have been shown to retain capacity of differentiation and also in a subpopulation of oligodendrocytes. In the peripheral nervous system CRMPs are expressed in a subset of sensory neurons and Schwann cells.

#### Immunologic associations

Patients with paraneoplastic syndromes and anti-CV2 antibodies may develop concurrent antibodies to other onconeural antigens. They include anti-Hu, anti-amphiphysin, anti-Ri, and anti-Zic4 antibodies.

#### **2.2.5 Anti-Ma antibodies**

The Ma proteins (Ma1, Ma2 and Ma3) belong to a family of brain-testis-cancer proteins. Ma1 and Ma2 antigens are expressed in the testis and in neurons. The highest level of expression of Ma antigens is seen in the neurons of the limbic structures, tegmental nuclei and cerebellar dentate nucleus. Aberrant expression of Ma antigens are seen in other malignancies, such as breast cancer (Sutton & Winer, 2002; Voltz, 2002).

Different neurological syndromes can be associated. Logically, mostly paraneoplastic limbic encephalitis and paraneoplastic encephalomyelitis are seen.

#### **2.2.6 Anti-amphiphysin antibodies**

The antigen is a protein located in synaptic vesicles and may have a role in vesicle endocytosis. This antibody is found in patients with Stiff-person syndrome, encephalomyelitis and subacute sensory neuronopathy. The underlying tumour can be breast cancer, as well as SLCL (Titulaer et al, 2011; Voltz, 2002).

#### **2.2.7 Anti-Tr antibodies**

This antibody has similarities with the anti-Yo antibody but can be differentiated by a typical immunohistochemical staining pattern of the molecular layer of the cerebellar cortex, in combination with staining of the Purkinje cell layer. Clinical presentation is a cerebellar degeneration. The associated tumour is Hodgkin lymphoma (Sutton & Winer, 2002; Voltz, 2002).

#### **2.2.8 Antibodies that occur with and without malignancy**

Anti-VGCC antibodies (anti-voltage gated calcium antibodies)

This antibody is mostly associated with LEMS. In 50% of patients with LEMS and anti-VGCC antibodies, SCLC is found. Rarely, patients present with a paraneoplastic cerebellar degeneration.

Anti-NMDAR antibodies (anti-N-Methyl-D-Asparginic acid receptor antibodies)

These antibodies are found in young women with a teratoma of the ovary. Clinically, patients present with a limbic encephalitis in combination with psychiatric symptoms and autonomic dysfunction. The neurological symptomatology can reverse after treatment of the tumour, as well as after immunotherapy.

Anti-Zic antibodies

98 Miscellanea on Encephalopathies – A Second Look

The tumour most commonly found in patients with anti-CV2 antibodies, is SCLC (60%- 77%). Further, thymoma (7%) and neoplasm of the uterus need to be excluded (Voltz, 2002).

The target of anti-CV2 antibodies is a family of ~66 kDa proteins that are mainly expressed in the nervous system called CRMP for Collapsin Response Mediator Proteins. In the adult brain, the expression of CRMPs is dramatically down-regulated. However, they remain expressed in structures that have been shown to retain capacity of differentiation and also in a subpopulation of oligodendrocytes. In the peripheral nervous system CRMPs are

Patients with paraneoplastic syndromes and anti-CV2 antibodies may develop concurrent antibodies to other onconeural antigens. They include anti-Hu, anti-amphiphysin, anti-Ri,

The Ma proteins (Ma1, Ma2 and Ma3) belong to a family of brain-testis-cancer proteins. Ma1 and Ma2 antigens are expressed in the testis and in neurons. The highest level of expression of Ma antigens is seen in the neurons of the limbic structures, tegmental nuclei and cerebellar dentate nucleus. Aberrant expression of Ma antigens are seen in other

Different neurological syndromes can be associated. Logically, mostly paraneoplastic limbic

The antigen is a protein located in synaptic vesicles and may have a role in vesicle endocytosis. This antibody is found in patients with Stiff-person syndrome, encephalomyelitis and subacute sensory neuronopathy. The underlying tumour can be

This antibody has similarities with the anti-Yo antibody but can be differentiated by a typical immunohistochemical staining pattern of the molecular layer of the cerebellar cortex, in combination with staining of the Purkinje cell layer. Clinical presentation is a cerebellar degeneration. The associated tumour is Hodgkin lymphoma (Sutton & Winer, 2002; Voltz, 2002).

This antibody is mostly associated with LEMS. In 50% of patients with LEMS and anti-VGCC antibodies, SCLC is found.

Antigen

This antibody has a low frequency. A variety of neurological symptoms can occur, with cerebellar ataxia due to paraneoplastic cerebellar degeneration most frequently seen. Underlying tumour is SCLC.

Anti-mGluR1 receptor antibodies

This metabotropic glutamate receptor antibody reacts with the mGluR1 receptor on the surface of Purkinje cells. There is an association with Hodgkin's lymphoma. Clinical presentation is a cerebellar syndrome (Darnell & Posner, 2003).

Anti-VGKC antibodies (anti-voltage gated potassium channel antibodies)

Patients with a positive serology for this antibody present typically with neuromyotonia. A PNS of the central nervous system occasionally seen is limbic encephalitis, commonly evolving to a less focalized encephalitis. Underlying tumours are SCLC and thymoma (Titulaer et al, 2011).

Anti-GAD antibodies (anti-glutaminic acid decarboxylase antibodies)

This antibody has a well known association with Stiff-Person Syndrome. Recently patients with paraneoplastic cerebellar degeneration or limbic encephalitis were described. This antibody is frequently found in patients with insulin-dependent diabetes mellitus. When a paraneoplastic mechanism is suspected, patients should be screened for a thymoma.

#### **2.3 Immune-mediated paraneoplastic syndromes of the central nervous system**

As 2/3 of PNS precede the diagnosis of malignancy, it is important to recognize the clinical picture and to start an appropriate screening for neoplasm.

Several features are shared by most PNS of the CNS. The clinical presentation is a fast accumulation of symptoms of central nervous system involvement, evolving over weeks and severely disabling the patient.

MRI findings are non-specific and can show normal findings, relative atrophy of specific regions (e.g. cerebellum) or regional Gadolinium-enhancing lesions. In cerebrospinal fluid, mostly signs of inflammation or immune-mediated mechanisms are withheld: moderate lymphocytic pleocytosis (30-40 white blood cells/mm3), increased protein concentration (50-100 mg/dl), high IgG index and CSF-specific oligoclonal bands (Darnell & Posner, 2003).

Because of the low prevalence of PNS, the PNS Euronetwork published diagnostic criteria for PNS (table 4) (PNS Euronetwork, 2002; Titulaer et al, 2011).

Neoplasm Related Encephalopathies 101

cerebellar involvement, whereas others are non-specific and might reflect a tumour-induced immune response. Dependent on the associated antibody, the clinical course, prognosis and

Most frequently, anti-Yo antibodies are seen, with ovarian cancer or breast cancer as underlying pathology. This PNS occurs consequently more in middle aged women. Median survival of anti-Yo positive patients with breast cancer is 100 months, whereas anti-Yo

When small-cell lung cancer is found, anti-Hu antibodies are present in 23-40% of patients with paraneoplastic cerebellar degeneration. Median survival is 9 to 12 months (Voltz, 2002). 41% of patients will develop anti-VGCC (voltage-gated calcium-channel) antibodies. These

Anti-Tr antibody, associated with Hodgkin's lymphoma, is another highly specific antibody. The patients are usually young men and the diagnosis of PNS often follows the diagnosis of

Rarely other antibodies are found, such as antibodies against collapsing-response mediator protein 5 (CRMP or CV2), amphiphysin or antineuronal nuclear antibody 3 (ANNA3).

The neuropathological hallmark of the paraneoplastic cerebellar degeneration is extensive loss of Purkinje cells in association with atrophy of granular and molecular layers. Microglial proliferation is seen in combination with astrocytosis. More specific, in the beginning of the disease T-cell infiltration in leptomeninges and in cerebellar cortex can be found. As the disease progresses, lymphocytic infiltration diminishes and gliosis develops

Paraneoplastic encephalomyelitis (PEM) has a strong association with the anti-Hu antibody (Titulaer et al, 2011). In 75% of patients with a positive serology, an underlying SCLC is found. Other antibodies less frequently associated with PEM are anti-CV2 (CRMP5) and

This PNS includes a variety of neurological syndromes, the clinical picture being the result of the variable anatomic involvement. The regions which are frequently involved are the hippocampus, lower brain stem, spinal cord and dorsal root ganglia (Gozzard & Maddison, 2010). The diversity of neurological dysfunction reflects the fact that anti-Hu antigens, the target of the autoimmune dysfunction, are expressed in all central and peripheral neurones

Most frequently, patients present with symptoms suggestive of subacute sensory

Patients present often with a symptomatology of one of the above mentioned regions, which eventually, as disease progresses, evolves into a multifocal neurological syndrome (PNS

As limbic encephalitis is part of this clinical picture often accompanied with an

neuronopathy, followed by limbic encephalitis, brain stem encephalitis and myelitis.

positive patients with ovarian malignancies survive 22 months.

antibodies are also present in Lambert-Eaton myasthenic syndrome.

(Dalmau et al, 2007; Nath & Grant, 1997; Sutton & Winer, 2002).

encephalopathic syndrome, this will be discussed further.

survival may differ (Voltz, 2002).

lymphoma (Nath & Grant, 1997).

**2.3.2 Paraneoplastic encephalomyelitis**

anti-amphiphysin.

(Sutton & Winer, 2002).

Euronetwork, 2002).

#### Diagnostic Criteria for Paraneoplastic Neurological Syndromes

#### Definite PNS

Possible PNS

Table 4. Diagnostic Criteria for Paraneoplastic Neurological Syndromes (Graus et al, 2004)

#### **2.3.1 Paraneoplastic cerebellar degeneration**

Although one of the best known PNS, paraneoplastic cerebellar degeneration is rare, occurring in 0,2% of patients with cancer.

The clinical presentation is typical. The progression of a paraneoplastic cerebellar degeneration is fast, leaving the patient severely disabled after a small number of weeks.

Patients start complaining of vertigo, dizziness and nausea, followed by ataxia which makes it difficult to walk and to perform activities in daily living. As disease progresses, nystagmus develops causingblurry vision, and dysarthria and dysphagia may occur.

About 20% of patients present with mild cognitive deficits (Gozzard & Maddison, 2010).

Initially MRI is normal. However, subsequent MRI scans during the course of the disease, show a progressive cerebellar atrophy. Initial fluoro-deoxy-glucose PET can show cerebellar hypermetabolism. The findings in cerebrospinal fluid are compatible with an immune mediated or inflammatory process (Gozzard & Maddison, 2010).

Differential diagnosis includes viral cerebellitis, toxic cerebellitis, alcohol-related vitamin deficiency induced cerebellitis and Creutzfeldt-Jakob disease (CJD) (Dalmau et al, 2007).

In the differential diagnosis with CJD, it is important to consider that 12% of patients with PNS of the CNS have 14-3-3 protein in the CSF whereas high titres of this protein in cerebrospinal fluid are typically found in CJD.

In patients with paraneoplastic cerebellar degeneration, a range of antineuronal antibodies can be detected in serum and in cerebrospinal fluid. Some are specifically related to

1. A classical syndrome and cancer that develops within five years of the diagnosis

2. A non-classical syndrome that resolves or significantly improves after cancer treatment without concomitant immunotherapy, provided that the syndrome is

3. A non-classical syndrome with onconeural antibodies (well characterised or not) and cancer that develops within five years of the diagnosis of the neurological

4. A neurological syndrome (classical or not) with well characterised onconeural antibodies (anti-Hu, Yo, CV2, Ri, Ma2, or amphiphysin), and no cancer.

1. A classical syndrome, no onconeural antibodies, no cancer but at high risk to

2. A neurological syndrome (classical or not) with partially characterised

3. A non-classical syndrome, no onconeural antibodies, and cancer present within

Table 4. Diagnostic Criteria for Paraneoplastic Neurological Syndromes (Graus et al, 2004)

Although one of the best known PNS, paraneoplastic cerebellar degeneration is rare,

The clinical presentation is typical. The progression of a paraneoplastic cerebellar degeneration is fast, leaving the patient severely disabled after a small number of weeks.

Patients start complaining of vertigo, dizziness and nausea, followed by ataxia which makes it difficult to walk and to perform activities in daily living. As disease progresses,

Initially MRI is normal. However, subsequent MRI scans during the course of the disease, show a progressive cerebellar atrophy. Initial fluoro-deoxy-glucose PET can show cerebellar hypermetabolism. The findings in cerebrospinal fluid are compatible with an immune

Differential diagnosis includes viral cerebellitis, toxic cerebellitis, alcohol-related vitamin deficiency induced cerebellitis and Creutzfeldt-Jakob disease (CJD) (Dalmau et al, 2007).

In the differential diagnosis with CJD, it is important to consider that 12% of patients with PNS of the CNS have 14-3-3 protein in the CSF whereas high titres of this protein in

In patients with paraneoplastic cerebellar degeneration, a range of antineuronal antibodies can be detected in serum and in cerebrospinal fluid. Some are specifically related to

nystagmus develops causingblurry vision, and dysarthria and dysphagia may occur.

mediated or inflammatory process (Gozzard & Maddison, 2010).

cerebrospinal fluid are typically found in CJD.

About 20% of patients present with mild cognitive deficits (Gozzard & Maddison, 2010).

Diagnostic Criteria for Paraneoplastic Neurological Syndromes

not susceptible to spontaneous remission.

of the neurological disorder.

have an underlying tumour.

two years of diagnosis.

**2.3.1 Paraneoplastic cerebellar degeneration**

occurring in 0,2% of patients with cancer.

onconeural antibodies and no cancer.

Definite PNS

Possible PNS

disorder.

cerebellar involvement, whereas others are non-specific and might reflect a tumour-induced immune response. Dependent on the associated antibody, the clinical course, prognosis and survival may differ (Voltz, 2002).

Most frequently, anti-Yo antibodies are seen, with ovarian cancer or breast cancer as underlying pathology. This PNS occurs consequently more in middle aged women. Median survival of anti-Yo positive patients with breast cancer is 100 months, whereas anti-Yo positive patients with ovarian malignancies survive 22 months.

When small-cell lung cancer is found, anti-Hu antibodies are present in 23-40% of patients with paraneoplastic cerebellar degeneration. Median survival is 9 to 12 months (Voltz, 2002).

41% of patients will develop anti-VGCC (voltage-gated calcium-channel) antibodies. These antibodies are also present in Lambert-Eaton myasthenic syndrome.

Anti-Tr antibody, associated with Hodgkin's lymphoma, is another highly specific antibody. The patients are usually young men and the diagnosis of PNS often follows the diagnosis of lymphoma (Nath & Grant, 1997).

Rarely other antibodies are found, such as antibodies against collapsing-response mediator protein 5 (CRMP or CV2), amphiphysin or antineuronal nuclear antibody 3 (ANNA3).

The neuropathological hallmark of the paraneoplastic cerebellar degeneration is extensive loss of Purkinje cells in association with atrophy of granular and molecular layers. Microglial proliferation is seen in combination with astrocytosis. More specific, in the beginning of the disease T-cell infiltration in leptomeninges and in cerebellar cortex can be found. As the disease progresses, lymphocytic infiltration diminishes and gliosis develops (Dalmau et al, 2007; Nath & Grant, 1997; Sutton & Winer, 2002).

#### **2.3.2 Paraneoplastic encephalomyelitis**

Paraneoplastic encephalomyelitis (PEM) has a strong association with the anti-Hu antibody (Titulaer et al, 2011). In 75% of patients with a positive serology, an underlying SCLC is found. Other antibodies less frequently associated with PEM are anti-CV2 (CRMP5) and anti-amphiphysin.

This PNS includes a variety of neurological syndromes, the clinical picture being the result of the variable anatomic involvement. The regions which are frequently involved are the hippocampus, lower brain stem, spinal cord and dorsal root ganglia (Gozzard & Maddison, 2010). The diversity of neurological dysfunction reflects the fact that anti-Hu antigens, the target of the autoimmune dysfunction, are expressed in all central and peripheral neurones (Sutton & Winer, 2002).

Most frequently, patients present with symptoms suggestive of subacute sensory neuronopathy, followed by limbic encephalitis, brain stem encephalitis and myelitis.

Patients present often with a symptomatology of one of the above mentioned regions, which eventually, as disease progresses, evolves into a multifocal neurological syndrome (PNS Euronetwork, 2002).

As limbic encephalitis is part of this clinical picture often accompanied with an encephalopathic syndrome, this will be discussed further.

Neoplasm Related Encephalopathies 103

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

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.

The two main clinical syndromes associated with these antibodies are typical limbic encephalitis and encephalitis with psychiatric symptoms, hallucinations and peripheral

About 30% of patients with anti-VGKC antibodies have tumours, of which SCLC and

The CSF of those patients shows less inflammation, less pleiocytosis and lower protein

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

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

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

Clinical symptoms often have an acute onset and may fluctuate in the development of the

Opsoclonus-myoclonus-ataxia syndrome can occur in combination with infections,

metabolic disturbances, toxic factors as well as in combination with neoplasm.

Limbic encephalitis with antibodies to neuronal cell-surface antigens

nerve hyperexcitability, amongst other signs of autonomic dysfunction.

Antibodies act against the voltage-gated potassium channels.

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

trunk. Occasionally, encephalopathy or cerebellar ataxia is present.

(neuromyelitis optica).

thymoma are most prevalent.

concentration compared to other PNS.

80% of patients respond to immunotherapy.

to supported ventilation or pace-making.

mostly in neurological improvement.

PNS. Rarely, it resolves spontaneously.

CSF studies may show pleocytosis and elevated protein levels. MRI brain scans are mostly normal. However, hyperintense T2-weighted lesions in brainstem, thalamus and hippocampus can be seen. Lesions are rarely contrast enhancing.

Extensive neuronal loss is seen in the affected brain regions: hippocampal sclerosis, gliosis in brainstem, spinal cord and dorsal root ganglia.

#### **2.3.3 Paraneoplastic limbic encephalitis**