Technische Universität München, Fakultät für Medizin Comprehensive analysis of current knowledge of Nodding Syndrome Kathrin Maria Miehle Vollständiger Abdruck der von der Fakultät für Medizin der Technischen Universität München zur Erlangung des akademischen Grades eines Doktors der Medizin (Dr. med) genehmigten Dissertation. Vorsitzender: Prof. Dr. Ernst Rummeny Prüfer der Dissertation: 1. Prof. Dr. Bernhard Hemmer 2. Priv.-Doz. Dr. Jan St. Kirschke Die Dissertation wurde am 25.01.2018 bei der Technischen Universität München eingereicht und durch die Fakultät für Medizin am 20.02.2019 angenommen. Table of contents Table of contents ......................................................................................................................... 1 Directory of abbreviations ............................................................................................................ 4 Acknowledgements ...................................................................................................................... 5 1. Abstract ................................................................................................................................ 5 2. Introduction.......................................................................................................................... 6 3. Methods ............................................................................................................................... 6 3.1 Search results for Nodding syndrome ..................................................................................... 6 3.2 Search results for Nakalanga syndrome .................................................................................. 9 Part I: Literature research on Nodding syndrome 4 Nodding syndrome: Results ................................................................................................. 12 4.1 Demographic and geographical features .............................................................................. 12 4.1.1 Affected age group ........................................................................................................ 12 4.1.2 Distribution across the sexes ......................................................................................... 12 4.1.3 Tribal distribution .......................................................................................................... 12 4.1.4 Familial clustering .......................................................................................................... 12 4.1.5 Geographical distribution .............................................................................................. 12 4.1.6 Interpreting figures on Nodding syndrome prevalence ................................................ 15 4.2 Clinical presentation .............................................................................................................. 15 4.2.1 Nodding episodes .......................................................................................................... 15 4.2.2 Cognitive impairment .................................................................................................... 16 4.2.3 Psychiatric signs/symptoms .......................................................................................... 17 4.2.4 Malnutrition, stunting and wasting .............................................................................. 17 4.2.5 Stunting, wasting and impaired sexual development ................................................... 18 4.2.6 Other signs/symptoms .................................................................................................. 18 4.2.7 Prognosis ....................................................................................................................... 18 4.3 Diagnostic findings ................................................................................................................ 19 4.3.1 Cerebro-spinal fluid ....................................................................................................... 19 4.3.2 Infections ....................................................................................................................... 20 4.3.3 Electroencephalography ................................................................................................ 24 4.3.4 Magnetic resonance imaging and computed tomography ........................................... 27 4.3.5 Histopathologic findings ................................................................................................ 28 4.3.6 Other findings ................................................................................................................ 28 4.4 Treatment .............................................................................................................................. 30 1 4.4.1 Antiepileptic drugs ............................................................................................................... 30 4.4.2 Immunomodulatory therapy ......................................................................................... 31 4.4.3 Other treatment goals ................................................................................................... 31 4.4.4 Treatment according to severity of disease .................................................................. 33 4.5 Prognosis/natural history ...................................................................................................... 33 4.5.1 Tanzania ......................................................................................................................... 33 4.5.2 Uganda........................................................................................................................... 34 4.5.3 South Sudan ................................................................................................................... 34 4.5.4 Conclusion ..................................................................................................................... 34 4.6 Management at national and international level ................................................................. 35 4.6.1 South Sudan ................................................................................................................... 35 4.6.2 Uganda........................................................................................................................... 35 4.7 Community perspective ........................................................................................................ 35 4.7.1 Nodding syndrome in Tanzania ..................................................................................... 35 4.7.2 Nodding syndrome in South Sudan ............................................................................... 35 4.7.3 Nodding syndrome in Uganda ....................................................................................... 35 5. Discussion of potential pathomechanisms in Nodding syndrome .......................................... 38 5.1 Onchocerciasis ....................................................................................................................... 38 5.1.1 The fight to control onchocerciasis ............................................................................... 38 5.1.2 Strains of O. volvulus and clinical manifestations of onchocerciasis ............................ 38 5.1.3 Pathogenetic concepts regarding the link between onchocerciasis and Nodding syndrome ....................................................................................................................................... 39 5.2 Measles .................................................................................................................................. 40 5.3 Other infectious diseases ...................................................................................................... 41 5.4 Toxins ..................................................................................................................................... 41 5.5 Malnutrition and vitamin B6 deficiency ................................................................................ 41 5.6 Metabolic causes and mitochondriopathy ............................................................................ 42 5.7 Psychiatric disorders .............................................................................................................. 42 5.8 Genetic predisposition .......................................................................................................... 43 5.9 Proposed approach to future research and treatment ......................................................... 44 Part II: Literature research on Nakalanga syndrome and a comparison to Nodding syndrome 6. Nakalanga syndrome........................................................................................................... 45 6.1 The ters of „Nakalaga ad „Noddig sydroe ........................................................... 45 6.2 Characterization of Nakalanga syndrome and a proposed definition .................................. 47 2 6.3 Information on etiology and possible causes of Nakalanga syndrome ................................. 51 6.4 Comparison between Nakalanga syndrome and Nodding syndrome ................................... 52 6.5 Conclusions and recommendations ...................................................................................... 56 7. Summary ...........................................................................................................................