The outcome of PKU: the relevance of neuroimaging and neurophysiological examinations. Vincenzo Leuzzi

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1 Department of Pediatrics and Pediatric Neurology and Psychiatry The outcome of PKU: the relevance of neuroimaging and neurophysiological examinations Vincenzo Leuzzi

2 The aims of the neuroimaging and neurophysiologic examination in PKU a) to explore neuro-physiologic/-anatomic background of clinical features (neurological status IQ, Executive Functions, etc) b) to identify a set of neuro-anatomic/-physiologic alterations which anticipates the clinical outcome (normal/abnormal IQ, EFs, etc) c) to identify a set of neuro-anatomic/-physiologic preclinical alterations reflecting the individual vulnerability to Phe

3 Signal transmission in CNS: transversal studies Reference Korinthenberg et al, Neuropediatrics 1988;19: Giovannini et al, J Inher Metab Dis 1988;11: Ludolph et al, Acta Neurol Scand 1992;85: Lou et al, J Inher Metab Dis 1992: 15: Leuzzi et al, J Clin Neurophysiol 1994;11:1-5 Cleary et al, Lancet, 1994;344:87-90 Jones et al, J Neurol Neurosurg Psych 1995; 59: Ludolph et al, Eur J Pediatr 1996;155:S64-S68 Pietz et al, Radiology 1996;201: Leuzzi et al, J Inher Metab Dis 1998:21: McDonnell et al, Eur Neurol 1998;39:38-43 Röricht et al, J Neurol 1999;246:21-30 PR-VEP, BAEP PR-VEP Neurophysiol test NCV, BAEP, PR-VEP, SEP, MEP PR-VEP BAEP, SEP, PR-VEP NCV, PR-VEP, SEP, MEP PR-VEP NCV, BAEP, PR-VEP, SEP, MEP PR-VEP PR-VEP (different spatial frequencies and visual contrast) PR-VEP, SEP, focal TMS

4 VEP alterations in PKU patients Ref. age (yrs) altered/exam ined Korinthemberg et al, 1993 % 16.2±2.8 9/25 36 Giovannini /14 0 Ludolph et al /22 31 Lou et al /16 0 Cleary et al /48 16 Jones et al / > 14 1/9 22/27 Leuzzi et al /22 13 Ullrich et al, /9 0 Pietz et al /51 18 Ludolph et al /33 27 Leuzzi et al /42 (eyes) McDonnel, 1998 > 18 14/

5 VEP alterations in PKU patients: Critical points Most of pts older than 10 Feeble or no discriminating power for early vs late treated pts (Leuzzi 1994, Jones 1995, Ludolph, 1996, Leuzzi 1998) Conflicting results No association with historical and concurrent quality of dietary control (QDC) (Ludolph 1992, Ludolph, 1996) Association with historical QDC (Korinthenberg et al 1988, Leuzzi 1994) Association with recent and/or concurrent QDC (Giovannini 1988) IQ and VEP Phe threshold effect: 900 μm (Leuzzi 1998), 1200 μm (Jones 1996) no association (Leuzzi, 1994) association with VEP amplitude (Jones, 1996) Remarks: different experimental designs, selection criteria, ages, biochemical control and outcome measures.

6 EPs - Longitudinal studies Pueschel et al, J Men Def Res 1983;27:61-67 Cardona et al, EEG and Clin Neurophysiol 1991; 80:8-15 Ullrich et al, J Inher Metab Dis 1994;17: Lou et al, Acta Paediatr 1994;83: Ullrich et al, 1996, Eur J Pediatr 155:S74-S77 Beblo et al, Neurology;2001;57: Agostoni et al, Arch Dis Child 2003;88:582-58

7 EPs: Longitudinal studies Postnatal delayed maturation of BAEP (I-V interpeak latency ) and F-VEP (N1 and P2 latencies) during the 1 st year of life; no correlation with biochemical/clinical parameters (Cardona et al 1991)

8 Postnatal delayed maturation of BAEP and F-VEP age of diet onset 42.25±52.47 IDC ±21.48 DQ 12 mo 95.8±13.3 Cardona et al 1991

9 EPs: Longitudinal studies Postnatal delayed maturation of BAEP (I-V interpeak latency ) and F-VEP (N1 and P2 latencies) during the 1 st year of life; no correlation with biochemical/clinical parameters (Cardona et al 1991) No variations of VEP, SEP, and BAEP after diet discontinuation at the age of 5 (Pueschel et al, 1983) No variation of VEP after 2 yrs of free diet and supplementation with Tyr, Trp, and essential amino acids (Lou et al, 1994) VEP P100 latency, sustained attention, and frontal lobe functions were not affected by 4 weeks of L-DOPA/Carbidopa administration (Ulrrich et al, 1994, 1996) No variation of F-VEP and BAEP after an oral PHE loading test (180 mg/kg bw/72 hrs) at the age of 6, 12, and 18 months (Leuzzi et al, unpublished data) VEP improved in PKU patients (but not in controls) under omega-3 LC-PUFA supplementation (Beblo 2001, Agostoni, 2003)

10 Event-related potentials - ERPs aims: to explore the neural networks potentially involved in cognitive processing of information and their susceptibility to the biochemical alterations of PKU methods: to assess latency and amplitude of (early and) late evoked components associated with different sensorial and active discriminative tasks

11 Woodman, 2010

12 Woodman, 2010

13 Event-related potentials in PKU (Auditory) stimulus discrimination (P300) (Leuzzi et al 2000) (Visual) stimulus discrimination (P300) (Henderson et al 2000) Early sensory processing and inhibitory functions (visual Go- Nogo task in adults with PKU (Wiersema et al 2005, Moyle et al 2006) Visual selective processing task: stimulus encoding and target selection/detection (de Sonneville et al 2010)

14 Ref age (yrs) patients on/off diet scre/ nonscre Biochemic al control (Phe mm) H (historical) C (closer or concurrent ) Task and ERPs RESULTS (A: amplitude L: Latency) INTERPRETATION Leuzzi et al /15 11/4 C on diet C off diet auditory discriminative P300 non-evocable in late treated and off diet pts A and L in early detected PKU on diet IQ is lower in patients with non-evocable P300 prefrontal cortex involvement Henderson et al /0 22/0 H C visual discriminative P300 (N170, P100) normal ( L N170 /P100) impairment of early sensory processing Wiersema et al /0 7/0 H 264±187 C 297±165 fast and slow Go/noGo choice P300 A and L in fast (+) and slow (++) operating conditions (Go/No-Go choice) accuracy in fast and slow operating conditions no correlation with quality of dietary control problems with the inhibition of prepotent response Moyle et al (IQR 25-30) 0/9 9/0 H 688±80.9 C 1000± Go/noGo choice P100, N170, N2 normal RT and accuracy A of P100 and N170 no diff between Go-N2 and No-Go N2 A impairment of early sensory processing and inhibitory functions de Soneville et al ± /0 42/0 C 477±253 H 16 pts 232±101 H 26 pts 672±191 orientation and spatial frequency discrimination P100, N170 N90, P180 N280 P425 (P300) normal early sensory components, RT, P300, A N90 no modulation of P180 A as function of the stimulus + N90 in PKU with Phe > 360 Accuracy: PKU Phe H > 360 Accuracy increase with the age in PKU H Phe N90, P180, N280 concurrent Phe N90, P180, N280 altered target detection impairment of selective attention? H Phe influences selective attention components

15 EP and ERP in PKU: conclusions The time resolution is the main advantage of EP and ERP studies Lack of knowledge on neurophysiological background of EP and ERP alterations and of their relevance on the outcome of the disease The linkage between ERP and IQ remains to be explored: are ERP alterations expressed by the IQ or do reflect an adjunctive disorder? Non longitudinal data available: are EP and/or ERP transient (maturational) or persistent (lesion) alterations? What the consequences (if any) of EP and/or ERP alterations in the real life? Future perspectives: a)longitudinal studies b)integrated neuropsychological and neurophysiological studies c)assessment of the sensitivity of EP and ERP to the biochemical alterations of PKU.

16 WM alterations (WMA) and neurological deterioration in PKU patients Neurological deterioration in adult PKU. Villasana et al, J Inher Met Dis, 1989: Neurological deterioration in young adults with phenylketonuria. Thompson et al, Lancet 1990;336: Unexpected white matter changes in an early treated PKU case and improvement after diet treatment. Battistini et al, Funct Neurol 1991;6: Spasticity and white matter abnormality in adult phenylketonuria. McCombe et al, JNNP 1992;55:

17 Neurological deterioration in young adults with phenylketonuria 11 pts Diagnosis: scr/non-scr 7/4 Age at onset (yrs) In/out diet 2/9 Gap diet stopping-disease onset 8 mo-16 yrs Previous learning/mental disorders 7/11 Previous neurological disorders 3/11 Presentation Brisk reflexes 9/11 Spastic parapesis/quadriparesis 4/11 Mental deterioration 4/11 Behavioural disorders 4/11 Intention tremor, ataxia 4/11 Epilepsy 3/11 Dystonia 1/11 Dorsal column sensory loss 1/11 CSF (4/11): HVA, 5-HIAA, MHPG (2/2)

18 WMA and neurological deterioration: clinical follow-up Ref. Case no Clinical and MRI outcome Thompson et al, ,5,6,7 diet therapy: clinical improvement in 3/4 cases (in 2 for more years); MRI improvement in 1/2 (2 months after starting therapy) Battistini et al, diet therapy: VEP, BAEP, and WM abnormalities regression (in a few months) Weglage et al, 1993 McCombe et al, diet therapy: clinical and MRI improvement (in 8 weeks) 1 diet therapy (Phe microm): clinical improvement B 12 supplementation: almost total normalization in 6 months (Phe values ) MRI abnormalities unchanged.

19 WMA in PKU without neurological deterioration Pearsen et al, Radiology 1990, 177: Bick et al, Eur J Pediatr, 1991;150: Shaw et al, AJNR, 1991;12: Lou et al, J Inher Metab Dis, 1992;15: Leuzzi et al, Neuroped, 1993;24:: Weaglage et al, J Inher metab Dis, 1993;16: Thompson et al, Brain;1993:116: Bick et al, 1993;152: Lou et al, Acta Paediatr,1994;83: Ulrich et al, Neuroped, 1994;25: Toft et al, I Inher Metab Dis, 1994;17: Cleary et al, Lancet, 1994;344: Leuzzi et al, J Inher Metab Dis, 1995:18: Pietz et al, Radiology 1996;201: Anderson et al, Dev Med Child Neurol 2004;46: Leuzzi et al, J Inher Metab Dis, 2007;30:

20 WMA in PKU without neurological deterioration: summary Patients: 344 Age range (yrs): </> 11 yrs: 42/185 (available data for 227/344) Type PKU (Phe > 600 µm): 332 Hphe (Phe< 600 µm): 12 Early/late detected 286/58 On/out diet: 135/209 Mental Dev normal/abnormal 128/59 (available data for 187/344) WM MRI normal/abnormal 28 (8.2%) / 316 (91.8%)

21 Variation of WMA under different Phe restriction 41 PKU patients (40 early treated) age 14 yrs: diet discontinuation yrs: brain WM alterations in 41/41 (Phe M) brain MRI 3-12 months later: Patient subgroups Strict diet (5) Low protein diet (21) No diet variation (15) Phe ( M) WM MRI score = 400 (70-800) ( ) ( ) MRI Phe (p>0.0002) MRI Phe at the time of the scan (p< 0001) Cleary et al, 1995

22 WMA and age in PKU patents (r.4667, p< 0.01) WM MRI score Age (yrs) Leuzzi et al, 2007

23 WMA and age (non-screening subjects) (r ; p<0.005) WM score WM T2 score Age (yrs)

24 ID/DOB CA 07/09/1985 FF 13/03/1984 MN 13/04/1980 MMT 06/10/1987 StSe 08/02/1985 AS 15/09/1987 CM 07/09/1977 PF 07/10/1982 SS 25/01/1987 Age (yrs/mo) WM MRI s Blood PHE ( M) 14/ / / / / / / / / / / / / / / / / / WMA score in subsequent exams WM score: 0 8= normal max severity

25 Phe mm % of maximum score Variation of WMA severity in subsequent exams 100 early detected PKU subjects (age 19.1±7.42 yrs, range ) 329 MRI scans (2 to 6 for each pt) Blood Phe values as function of the age WM involvement as function of the age Leuzzi & Walter, unpublished

26 Factors influencing WMA severity in subsequent exams 100 early detected PKU subjects (age 19.1±7.42 yrs, range ) 329 MRI scans (2 to 6 for each pt) a) Age of the patient at the first examination: higher variations of the score until the age of 30; lower variations over the age of 30 b) Time gap between the two subsequent examinations: > gap > WM score (or < improvement); c) The value of concurrent Phe at the final examination: > blood Phe > WM score (or < improvement) d) Females shows a major vulnerability than males (< WM improvement or > WM worsening)

27 The clinical significance of WMA non-significant influence of WMA on IQ (Pearsen 1990, Bick 1993, Leuzzi 1993,Wegleage 1995, Pietz 1996, Cleary 1994, Leuzzi 1995, Leuzzi 2007)

28 WMA severity and mental functioning vs 3.812; p=0.13

29 The clinical significance of WMA non-significant influence of WMAs on IQ (Pearsen 1990, Bick 1993, Leuzzi 1993,Wegleage 1995, Pietz 1996, Cleary 1994, Leuzzi 1995, Leuzzi 2007) (Anderson 2004) severe WMA impairment in IQ, divided attention, processing speed, verbal an visual learning, mental flexibility, reading, and arithmetic mild WMA impairment in IQ, reading and arithmetic performances no WMA impairment in IQ and processing speed Concl: WMAs result in compromised neural transmission

30 Neurophysiological studies and WMA in PKU 77 PKU pts aged (70/7 early/late treated; 19/58 on/out diet) MEP (55 pts): CMCT in 3/55 pts PR-VEP (48 pts): P100 latency in 8/48 pts SEP (46 pts): normal 46/47 pts MSNC (56 pts): NV 6/56 pts Conclusion: we were unable to show any relationship between the severity of neurophysiological abnormalities and severity of MRI changes Cleary et al, 1994

31 WMA and PKU: conclusions WMA occurs in a high percentage of PKU patients; WMA emerges at the end of the first decade of life and later stabilizes; WMA is not associated with unequivocal variations of the clinical status; WMA is not associated with unequivocal signs of myelin impairment or neural transmission derangement; WMA is correlated with: lifetime and concurrent Phe level, age (with a marked interindividual variability), and sex; WMA can be partially reversed by lowering blood Phe (with a marked interindividual variability) WMA emergence and vanishing are slow processes (lasting months)

32 Neuroimaging and neurophysiologic examination in PKU: conclusions a) clinical examination remains the most sensitive and reliable tool in predicting (and reflecting) the result of the treatment in PKU; b) neuroimaging and neurophysiologic tools have so far furnished a scarce contribution for the comprehension of the background of mental disorders in pts with PKU

33 Neuroimaging and neurophysiologic examination in PKU: future topics a) to explore neuro-anatomic/-physiologic background of clinical features (neurological status IQ, Executive Functions, etc) b) to identify a set of neuro-anatomic/-physiologic alterations which anticipates the clinical outcome (normal/abnormal IQ, EFs, etc) c) to identify a set of neuro-anatomic/-physiologic preclinical alterations reflecting the individual vulnerability to Phe

34 Blood Phe and intellectual phenotype in untreated phenylketonuria patients individual vulnerability to Phe SJ Ramus et al., 1999

35 F/13 yrs neonatal screening: Phe 240 μm PAH genotype: T380M/D151E infancy: psychomotor delay, motor difficulties, hypersalivation, aggressiveness > 5 yrs: episodes of ataxia gait and limb rigidity 11 yrs: mental retardation, ataxia, hypersalivation clinical improvement with neurotransmitter treatment

36 How to detect individual vulnerability in early treated PKU patients? To what extension does the individual vulnerability affect the outcome of PKU? Koch et al JIMD, 2002

37 it is much more important to know what kind of patient has a disease than to know what kind of disease the patient has Caleb H. Parry, M.D