Clinical Neuroscience - Overview

Illness Cause, symptoms, risk factors, progression Diagnostics Therapy, prevention

Multiple Sclerosis Autoimmune inflammatory, demyelinating, degenerative disease Presentations in MS: Only symptomatic treatment / mitigation of progression, in
of the central nervous system, immune cells attack the myelin  Visual: optic neuritis, INO (internuclear ophthalmoplegia: relapsing-remitting MS: suppression of the immune system,
sheaths, cause inflammation and thereby damage the nerves / Lähmungserscheinungen der Augenbewegungen), diplopia Alemtuzumab eradicates B- and T-cells, works beyond
axons (Störung des Binokularsehens) treatment, other drugs only while applied.
 Schädigung des Fasciculus longitudinalis im Mittelhirn,
risk factors: women more often affected than men, smoking, der das Zusammenspiel der Hirnnervenkerne, die die *MS-mimics:
genetics (HLA-DRB1*1501, IL2-receptor, IL7-receptor, …), Augenbewegungen steuern  ADEM (acute demyelinating encephalomyelitis): treatable
viral infections, retroviruses, somatic mutations, vitamin D  Motor: weakness, fatigability, progressive myelopathy (antibiotics, corticosteroids), usually full recovery,
deficiency / too little sun exposure, diet, geography (western (damage of the spinal cord due to pressure from bones), predominantly in childhood and adolescence, mainly post-
countries more often affected) incomplete transverse myelitis (transverse myelitis: infectious, rarely post-vaccination, monophasic course,
inflammation of the spinal cord) encephalopathy symptoms (impaired consciousness) and
Progression is very variable, generally 2 types: primary  Sensory: numbness, paraesthesia (non-painful sensation in multifactorial deficits
progressive or relapsing-remitting. a skin area without any visible adequate sensory input),  NMO (Neuromyelitis optica): not an MS-variant, part of
Relapse: focal disturbance of function, affecting a white matter pain, Lhermitte sign (push patient’s head to the front, MS-spectrum? Antibodies against Aquaporin 4, often
tract, lasting for more than 24 hours, typically tends to progress positive when this causes a painful, electrifying sensation in monophasic course, seldom chronic, patients get worse
over a period of a few days, reaching a maximum in less than 1 arms, torso or legs coming from the neck, verursacht when treated with MS-drugs
week and then slowly resolving / occurrence of a symptom / durch Verschiebung der schmerzempfindlichen Hirnhäute  Neurosacoidosis: stages I and II usually spontaneous self-
symptoms of neurological dysfunction in the absence of fever im Bereich der Wirbelsäule, kann auch durch Vitamin B12 healing, 2/3 subacute monophasic, 1/3 chronic-remitting,
(heat in general can worsen MS-symptoms), with or without Mangel verursacht warden), incomplete transverse myelitis if chronic therapy with corticosteroids and immune-
objective confirmation, lasting more than 24 hours suppressants
 Coordination: ataxia (=Unordnung, Unregelmässigkeit)
Relapsing-remitting type (mostly inflammation during this time)
 Gait: impaired, due to coordination problems  Susac-syndrome: causes unresolved, symptoms:
usually continues into the secondary progressive state (start of
 MRI: white spots, lesions, T1 hypointensities (some parts encephalopathy, vascular occlusion in the eyes, deafness,
demyelination and axonal loss), but brain atrophy starts early in
of the brain present darker than normal) looks exactly like MS in MRI, extremely rare
both types and persists throughout

long term disability: generally the higher the initial lesion load, Diagnostic criteria: Dissemination in space (lesions in ≥ 2 of 4
the worse the future disability progression areas of the CNS, e.g. optic neuritis and myelitis, brain and
spinal cord) and time (2 MRI pictures with some time in
Background on brain atrophy in MS: occurs at 5-10 times the between showing an increase in the number of lesions),
rate observed by ageing (0.1 – 0.3% per year), brain volume loss demonstrated by MRI
is used to assess neuro-axonal degeneration, atrophy correlates
significantly with physical disability and cognitive dysfunction, is Cerebrospinal fluid showing IgG (oligoclonal bands) 
predictive of future disability (maybe better than initial lesion inflammation, if missing, there might be a better explanation* (a
load measurements) treatable cause!) for the symptoms of the patient
Neuromuscular disorders and Symptoms: loss of strength, atrophy, fatigability, pain, Medical and family history (talk with patient), neurological Treatment of underlying disorder, immune-mediated
peripheral neuropathies numbness, tingling examination, lab-tests, muscle MRI, exercise tests: NIFET (non- neuromuscular disorders: steroids, cytostatic drugs, intravenous
ischemic forearm exercise test), SATET (sub-anaerobic immunoglobulins; treatment of concomitant disorders,
Nerve disorders: threshold exercise test)  anaerobic / lactate threshold; physiotherapy, Ergotherapie, Logopädie, splints (Schienen),
 Mononeuropathy: lesion of one single nerve due to echocardiography (ultrasound screening of the heart), pulmonary canes, social support
pressure or injury function testing (lungs), E(N)MG (electro(neuro)myography:
 Polyneuropathy: lesion of many nerves due to toxins electrophysiological screen of central motor functions, Polyneuropathy: treatment of underlying disorder (medication,
(alcohol, drugs, medication, …), metabolic disorders peripheral nerves, neuromuscular transmission and the muscles, blood sugar, thyroid, vitamin substitution, antibiotics, …),
(diabetes), inflammation, infection, autoimmune reaction, muscle biopsy antidepressants, anticonvulsants, physiotherapy, special care for
cancer, genetics (Charcot Marie-Tooth, a.o.), … feet: podiatry, ortheses, orthopedic shoes, check temperature of
Symptoms: very often tingling in the feet, missing or Polyneuropathy: search for treatable causes (lumbar puncture, water / sand / floor to prevent burns when walking barefoot,
wrong sensations, coordination problems genetics, tumor), time course, distribution (a-/symmetrical), keep feet clean and moisturized, daily inspection for injuries,
 Radiculopathy: nerve root lesion (spinal disc herniation = ENMG avoid walking barefoot
Einklemmung), most common cause for lumbar back pain:
lumbar disc herniation, in 20 -30 % of people below 60 Radiculopathy: MRI-screen, problem: is what’s visible on the Radiculopathy: physiotherapy, surgery in case of progredient
years, general back pain life time prevalence: 87%, rare scan really the cause of the symptoms? paresis (unvollständige Lähmung), bladder or bowel dysfunction
causes: tumors, bone metastases, inflammation, infection or if other therapy is unsuccessful, pain killers, behavioral
(Lyme radiculitis, …) therapy
 Plexopathy: brachial or lumbosacral nerve network
Carpal tunnel: wrist joint splint at night, injection of steroids
disorder due to tumors, radiation, immunological disorders
into the carpal tunnel, surgery
Carpal tunnel syndrome (mononeuropathy): most common
(without known cause), possible explanations: flexor tendon
entrapment syndrome (eingeklemmter Nerv), women more
inflammation, joint inflammation (polyarthritis), thyroid
often affected than men, 75% of patients > 40 years, pressure in
disorders, pregnancy, kidney insufficiency, diabetes; symptoms:
the carpal tunnel leads to compression of small arteries and veins
pain or pinprick-sensation in the hand expanding towards the
which causes small infarctions and swelling of the median nerve,
arm, at first during activity of the wrist, later on spontaneous, in
cause: idiopathic
advanced states muscular atrophy
Myotonic Dystrophy (DM) Hereditary (autosomal dominant), caused by repeat expansions Diagnosis: Family history, search for symptoms as described incurable, symptomatic treatment with drugs and gymnastics
in untranslated regions of 2 genes: below
Molecular mechanism of DM:
Curschmann Steinert disease (Myotonic Dystrophy type 1): Type 1 forms and symptoms:  repeat RNA accumulates in the nucleus of the affected
1/20’000, CUG repeats in 3’ UTR in DMPK (myotonic  mild / late onset / asymptomatic: 50-100 repeats, onset at tissues, can’t be degraded due to high stability  toxic
dystrophy protein kinase), normal repeat length: 5-37, pre- age 20+, life expectancy 60 - normal, symptoms: cataracts, (proof: CTG repeats in any gene leads to DM-like
mutation without symptoms: 38-50, affected: 50 – 4000, type 1 mild myotonia phenotype in transgenic mice)
more common, has an anticipation effect: symptoms get worse  late onset, classic: 50-1000 repeats, onset at age 10-30, life  haploinsufficiency not a primary cause for myotonia, but
and onset is earlier with longer repeats, most severe courses expectancy 48-60, symptoms: progressive muscle weakness for cataracts: reduced SIX5 levels in type 1 patients (six5
when inherited by mothers in face and neck area and the legs, myotonia, cataracts KO-mice develop cataracts)
(Linsentrübung), conduction defects, insulin insensitivity,  CUG-repeats form hairpin structures that bind
Myotonic dystrophy type 2: balding, respiratory failure, cardiac arrhythmias, hormonal muscleblind (MBNL), a factor required for alternative
CCUG repeats in 1st intron in ZNF9 (zinc finger 9), myotonic imbalances, in advanced states pain in the joints splicing that is usually evenly distributed, MBNL-KO-mice
dystrophy type 2, normal: 7-24, pre-mutation: 22-33, affected:  childhood onset: 50-1000 repeats, onset at age 1-10, develop cataracts and myotonia, overexpression / injection
75-11000, saturation-effect / somatic mosacism symptoms: facial weakness, myotonia, psychosocial of MBNL rescues myotonia in CUG-repeat expressing
problems, low IQ, conduction defects mice
 congenital (“sloppy infant”): 1000+ repeats, onset at birth,  CUG-binding protein is upregulated (gain of function),
symptoms: infantile hypotonia, respiratory failure, learning also an alternative splicing factor, together with low
disability, cardiorespiratory complications in 3rd and 4th MBNL levels generates DM phenotype: wrong alternative
decade splicing of insulin receptor (insulin resistance), chloride
channel (myotonia) and cardiac troponin (arrhythmias)
Amyotrophic lateral sclerosis More than 1 / 100’000 get ALS each year, progressive adult- No disease biomarkers for early diagnosis, prognosis and No available treatment
(ALS) onset disease, upper and lower motor neuron degeneration progression monitoring
(motor neuron loss in spinal cord), muscle weakness progressing Experimental treatment: antisense oligonucleotides
to paralysis and death typically within 1-5 years from onset only Diagnosis usually after 13-18 months after onset, 5-8% are
5-10% live longer than 10 years, ubiquitin protein inclusions in diagnosed wrong and 40-60% of patients with symptoms have a Therapy: logopedic therapy, ergotherapy, physiotherapy,
the spinal cord, 20% will develop frontotemporal dementia, 10% treatable disorder prophylaxis of pneumonia, early antibiotic treatment in case of
are inherited, 90% of cases occur sporadic (not inherited) of pneumonia, therapy of hypersalivation, treatment of respiratory
which another 10% can be explained by de novo mutations / Symptoms: painless paralysis of arms and legs, clumsiness, insufficiency, symptomatic treatment of dysarthria and other
incomplete family history seldom: trouble with speaking and swallowing, depending on the symptoms which might influence the quality of life (depression,
affected nerves cramps, pain, spasticity), medication: Riluzole, reduction of
2% of ALS cases are SOD1-mediated (not associated with cytotoxicity, slows the disease process but causes diarrhea,
FTD), mutation in superoxide dismutase 1, more than 170 Awaji criteria have a significant clinical impact allowing earlier vertigo, fatigue and nausea, high costs
different mutations in this gene cause ALS, ubiquitin inclusions diagnosis and clinical trial entry in ALS
contain SOD1, can be transmitted from cell to cell  Definite ALS: lower and upper motor neuron signs in at 3 important mechanisms: haploinsufficiency, hairpin formation,
least 3 body regions (bulbar, cervical, thoracic, lumbar) repeat-associated-non-ATG translation
Protein accumulations in 5% of familial ALS cases and 97% of  Probable ALS: lower and upper motor neuron signs in 2
all ALS cases contain TDP-43 (TAR-DNA-binding protein 43 body regions, upper motor neuron signs necessarily rostral Still unclear if FUS and TDP-43 are due to gain of function
kDa) as their major component, it is a RNA/DNA binding to the lower motor neuron signs (aggregation in the cytoplasm  toxic), loss of function (nuclear
protein with high aggregation propensity, contains a prion-like  Possible ALS: lower and upper motor neuron signs in 1 clearance  loss of normal function) or both, in healthy cells
or low complexity domain (Gly-rich region, important for stress body region, upper motor neuron signs in at least 2 regions they help with alternative splicing, mRNA stability and transport
granule formation)  ability to change conformation from or lower motor neuron signs rostral to upper motor and regulation of long intron containing pre mRNA, KO mice
globular to aggregated, common in RNA binding proteins, neuron signs don’t survive very long (embryonic lethal with TDP-43, FUS die
pathological posttranslational modifications lead to ALS, a few days after birth due to errors in B-cells
autosomal dominant missense mutation, >35 mutations in this Primary lateral sclerosis affects arms and legs, prognosis is
region are known to cause ALS, TDP-43 is found in stress much better than in ALS (higher median survival rate) In C9ORF72 KO doesn’t cause the disease, but RNA forms G-
granules: non-membranous cytoplasmic foci composed of non- quadruplexes and sequesters neucleonin (RNA binding protein,
translating messenger ribonucleoproteins that rapidly aggregate SBMA (Spinobulbar muscular atrophy): RBP), RNA aggregates, sense and antisense repeat RNA get
in cells exposed to stress X-chromosomal recessive, affects the lower motor neuron and translated, unclear which causes the disease: RBP loss of
leads to weakness, atrophy and fasciculation in the legs, shoulder function, C9ORF72 loss of function or C9ORF72 gain of toxic
The remaining 1% of cases is due to other unknown causes or a area and face function
mutation in FUS or TLS (fused in sarcoma / translocated in
liposarcoma), another RNA/DNA binding protein, autosomal MMN (multifocal motor neuropathy): In SOD1: probably gain of toxicity
dominant and recessive, mutations disrupt the nuclear Progressive asymmetric weakness with atrophy, no sensory
localisation signal (NLS), juvenile onset ALS associated with involvement, no signs of the 1st motor neuron, no bulbar
FUS mutations symptoms, GM1-antibodies in 30-80%, CSF protein may be
normal, perivascular lymphocytic infiltrate on nerve biopsy,
In 10% (4 / 10% in familial ALS and 6 / 90 % in sporadic ALS) prevalence 0.6-2 / 100’000, age at onset 20-50 years
of all ALS cases there is a mutation in C9ORF72, in these
patients the cerebellum is also affected, cause is a hexanucleotide Isaac’s syndrome: neurological autoimmune disease, affects the
repeat GGGGCC neuromuscular synapse, antibodies against K+-channels
Frontotemporal Dementia Most common cause of dementia under 60, 5-15 / 100’000 get it The microsatellite repeat C9ORF72 causes most of the 45% of cases are due to TAU, no motor neuron degeneration
(FTD) each year, progressive adult-onset brain disease, frontotemporal overlapping cases: mutation found in 29% of patients with FTD
lobar degeneration, behaviour changes including language and in 90% of families with FTD and ALS 9% of cases are due to FUS
dysfunction, emotional coldness and apathy, death within 2-10
years, typically no memory loss (unlike AD), ubiquitin protein TDP-43 mutations explain 45% of FTD cases, but aggregation is 1% are unknown causes
inclusions in the frontal lobe, 15% will develop motor neuron in the frontal cortex instead of the spinal cord
disease (Therapy and diagnostics no info provided / ALS)
Parkinson’s disease Risk factors: age, toxins (methane), smoking Diagnosis: primarily clinical: talking to the patient, family Treatment: Levodopa (can pass the blood brain barrier), gets
(PD) history, posture and tapping test, functional imaging, metabolized into dopamine in the brain (dopamine can’t pass the
Symptoms: sparse mimic, slow movement (akinesia) + at least polysomnography (sleep), trial and error: if treatment with blood brain barrier) + DA-carboxylase inhibitor (so that
one of the following: (rest) tremor (without gravitational dopamine helps, it must be PD Levodopa can reach the brain)
influence), rigidity, postural instability
Non-motor symptoms: dementia, apathy, depression, anxiety, PD starts in one hemisphere, if it’s symmetrical: probably not Levodopa +: strong, tolerable, cheap
sleep-wake disturbances (sleepiness, insomnia, REM-sleep PD! Levodopa – : long-term complications: motor fluctuations,
behaviour disorder: muscle tone doesn’t decrease during the dyskinesia and akinesia phases become longer over time,
night, result: patient acts out their dreams, often first sign, years Essential tremor: primarily postural and action tremor, gets “honeymoon phase” decreases
before onset of the first motor disorders), autonomic disorders better with alcohol and deep brain stimulation
(erectile dysfunction, incontinence, orthostatic dysregulation Dopamine Agonist +: less motor fluctuations
(blood pressure regulation fails when getting up), …), pain Holmes / midbrain tremor: combination of postural, action Dopamine Agonist – : expensive, causes sleepiness, edema,
(caused by the brain, treatable with dopamine) and rest tremor, due to cerebellar damage, can have an hallucinations, impulsive control disorders (sexuality, shopping,
underlying cause like stroke, brain tumor or other cerebellar gaming, gambling, punding (repetitive playing), eating, etc. all go
Protein aggregation (α-synuclein) due to wrong folding, Lewy lesions up)
bodies accumulate and the cells die, probably starts in the
autonomous nervous system (heart, intestines  constipation, Meige syndrome: dystonia, symmetrical cram-like contractions Deep brain stimulation: only applied in severe cases, stimulation
diarrhea) and rises upwards into the brainstem ( REM-sleep of face, jaw and pharyngeal muscles, mostly women in their 70- of subthalamic nucleus, progression might be slowed, symptoms
disorder) and finally into the brain ( motor disorders) ies decrease by 60%

Chorea: hyperkinetic, non-repetitive, no dystonia, very random

pattern (Chorea Huntington)
Epilepsy Chronic condition of repeated seizures Electroencephalogram (EEG): measurement of voltage Treatment and management: pharmacotherapy with
difference between 2 points, background rhythm: α-waves, anticonvulsive drugs that act on a cellular level (Na-channel
Causes: brain tumor, bleeding (oxidative stress due to iron), source: synaptic potentials of synchronized neurons (averaged blocker, GABA-agonists), surgical treatment: “mechanical
metabolic disease (e.g. too much Glu, imbalanced electrolytes, field potentials), spatial resolution: 5-9cm (volume-conduction solution” by removal of epileptic activity (usually hippocampus),
kidney / liver disease, …), electrolyte disorders, drugs (Ritalin, mixture), temporal resolution: dependent on the sampling rate vagal nerve stimulation (inhibitory signaling?) or deep brain
cocaine, …), concussion (traumatic brain injury TBI), genetic (1/200 to 1/10’000 s), filtering: soft tissue and bones are stimulation (seizure propagation?), disease specific treatment
disorders, inflammation, Kreuzfeld-Jakob-disease, Herpes equivalent to low pass filters  no action potentials are visible (e.g. immune-suppressive therapy in limbic encephalitis),
encephalitis (virus affects the hippocampus), visual stimuli (only in the EEG, only thousands of neurons firing at the same time ketogenic diet (useful in genetic forms of epilepsy)
in genetically affected patients) cause a spark on the EEG

Symptoms: generalized (tonic-clonic) or focal (depending on EEG image of epileptic activity: spike-wave-complex (looks
the brain area) seizures similar to EKG of heart)

Seizure: temporary disruptions of brain function resulting from Association between sleep and epilepsy:
abnormal, excessive neuronal activity, 1-2% of people 2/3 of seizures occur between 8pm and 8am, 21% of patients Sleep disturbances are more common in epilepsy, excessive
experience a seizure within their life not due to epilepsy experience seizures only at night, 42% only during the day and daytime sleepiness in up to 50%, obstructive sleep apnea in up to
Pathophysiology: focal seizures originate from enhanced 37% experience them randomly, peaks of seizures occur in 56%, restless leg syndrome in up to 33%, parasomnia with
excitability in a small group of neurons (epileptic focus), basic response to falling asleep and awakening, after 2 years of only variable frequency  affects quality of life in patients
mechanism: pathological (hyper)synchronisation is caused by a sleep-related epilepsy a patient is allowed to drive a car Epilepsy also affects sleep stages and overall “sleep
breakdown of surrounding inhibition between neurons  Most seizures occur during non-REM-sleep, only 0-5% occur architecture”, independent of presence or absence of seizures,
GABA receptors are the main target in epileptic medication, the during REM, 68% occur during non-REM2 which promotes treatment improves symptoms and sleep architecture
epileptic focus can be in different states: interictal (between secondary generalisation in temporal and occipito-parietal but
seizures), ictal (seizure) or status (ongoing seizure) not frontal lobe seizures
Focal and secondary generalized: seizures share the concept Sleep deprivation promotes seizures, especially in awakening
of a local seizure focus with possible spreading to the whole epilepsy, sleep duration correlates with seizure probability and
brain frequency, sleep deprivation causes seizures whereas sleep leads
Primary generalized: seizures are driven by pathological to epileptic discharges (no seizure)
cortical hyperexcitability and thalamocortical afferents
Sleep Normal sleep Paroxysmal (anfallsartig) behavioral events in sleep: sleep Sleepwalking: in children up to 10%, 2-4% in adults (de-novo
Sleep is defined behaviorally by four criteria: reduced motor related epileptic seizures, non-REM parasomnia (confused in adults only 0.6%), genetic predisposition, triggered by
activity, decreased response to activity, stereotypic postures and arousal, sleep terror, sleep walking), REM parasomnia (REM- medication, sleep deprivation, sleep disorders with arousals (e.g.
reversibility. Two major processes regulate sleep: circadian sleep behavior disorder  PD), paroxysmal hypogenic dystonia apnea), pregnancy, stress
rhythm (inner clock, influences deep sleep duration (movement disorder), nightmare disorder, sleep-related
independently of homeostasis due to hormonal changes) and dissociative disorder, sleep-related panic disorder, Clinical symptoms of sleepwalking: occurs during first half of the
homeostasis (time dependent: the longer we stay awake, the gastroesophageal reflux, sleep-related rhythmic movement night, disorientation, amnesia for the episode, often eyes are
more sleep we need). Sleep is organized in stages and cycles. disorder, catathrenia (moaning during REM-sleep) open, aggressive behavior possible, injuries are common
Important structures in sleep wake regulation are the thalamus Parasomnias: undesirable physical events or experiences that Therapy: secure environment (possible treatment: cognitive
(cortical activation, sleep spindle, EEG synchronized), medulla occur during entry, within or during arousals from sleep: behavioral therapy, low dose benzodiazepines, sedating
(ascending reticular activating system), pons (REM sleep abnormal sleep-related movements, behaviors, emotions, antidepressants, but evidence is weak, not recommended)
activation and control), subcortical nucleus (SCN, circadian perceptions, dreaming, autonomic nervous system functioning
clock), hypothalamus and cortex. Sleep helps in learning and Diagnosis is important because if the consecutive sleep REM-sleep behavior disorder (RBD): enactment of dreams,
memory. Stages and cycles: non-REM 1 (vertex waves), non- fragmentation and risk of injuries (bed partner can be affected!), in 0.5% of adults, observed in 50% of PD-patients, clinical
REM2 (K-complexes, sleep spindles), non-REM 3 (SWS, slow 3 types: non-REM (confused arousal, pavor nocturnus, characteristics: animated, threatening dreams leading to
wave sleep), REM-sleep (always at the end of each stage, one sleepwalking), REM (REM sleep behavior disorder) and aggressive behavior (hitting, kicking, grumbling, gesticulation,
stage lasts for ~90min. Sleep profile and need changes with age: overlapping laughing, crying, …), often serious injuries, usually during the
REM phase and sleep duration both decrease. Polysomnography last 1/3 of the night, associated with hallucinations, cognitive
measures brain activity (EEG), muscle activity, eye movements, impairment, vegetative symptoms, triggered by antidepressants,
breathing, heart activity (EKG), leg movements, snoring and alcohol or alcohol withdrawal, treatment medication and a
oxygenation. Also the patient is being videotaped to detect any secure environment
behavioral peculiarities.
Stroke Caused by bleeding or blood clotting, can lead to focal or global Every acute neurological symptom is a stroke, unless proven Immediate treatment: catheter into the clogged artery, controlled
clinical signs, symptoms: movement deficits (usually hemiplegic, otherwise! by X-ray-contrast, strategies for vascular reopening: intravenous
only one half of the body affected), dysarthria, headache, loss of Diagnostic tools: MRI and ultrasound (to detect bleeding) thrombolysis, intra-arterial thrombolysis, up to 6h after the
consciousness, usually no characteristic pain like in a heart attack incident
 difficult to detect! Time window: after 270 min (4.5 hours) the improvement after 4.5h – 2 weeks after the incident: prevention of further stroke,
stroke treatment is so minimal, that it’s statistically irrelevant… risk only declines after 2 weeks, possible brain swellings must be
Ischemia: 80% of cases, hemorrhagic transformation Also the more time passes, the higher the risk for hemorrhage treated with removal of skull parts (hemicraniectomy, saves the
Hemorrhage: 2015 of cases, intracerebral (85%) and within the dead tissue rest of the brain)
subarachnoid (15%) hemorrhage Because blood supply is different in every person, the time Later on: secondary prevention and neurorehabilitation
Ischemia and intracerebral hemorrhage cause cardinal window can be bigger or smaller
symptoms: acute hemiplegia, -paresis, aphasia, dysarthria, vertigo Prevention: antiplatelet-drugs (aspirin) prevents
or visual symptoms Prediction of outcome: hematoma volume, GCS (Glasgow coma thromboembolic clogs, anticoagulants prevent cardio-embolic
In subarachnoid hemorrhage symptoms are acute onset of scale), intraventricular hemorrhage, age, intracerebral clogs, healthy lifestyle: low blood fat values (prevention of
headache and/or loss of consciousness hemorrhage location, increased cerebral edema (midline shift, arteriosclerosis) and low blood pressure
% values for western countries, in Japan ischemia and herniation = Einklemmung)
hemorrhage are equally likely Sites of intracerebral hemorrhage usually where arteries divide in
Mechanism of injury: hematoma growth, increase in a 90° angle  pressure on the blood vessel walls, rupture more
Normal cerebral blood flow (CBF) 45-50 ml / 100g /min, intracerebral pressure, tissue disruption, shear forces, edema and likely, usually high mortality rate and limited recovery
membrane potential breakdown if CBF drops to 20ml, 25% of toxic effects of blood products, osmotically active serum
normal CBF leads to 95% stroke probability, 50% CBF ~5% products, thrombin, inflammatory response, hematoma
stroke probability, substrate depletion within minutes, expansion happens in 26% within 1h, 72% have some
accumulation of toxic metabolites expansion, 38% have significant expansion during the first 24h

Concept of the Penumra: Penumbra: moderate reduction of CBF, compensation by Oligemia: slight reduction of CBF, reduction in electrical function,
Infarct zone (core): massive reduction of CBF, early breakdown of collateral supply, reduction of cellular metabolism, reduction of cells remain viable
cellular metabolism, energy supply, ion homeostasis and energy supply, inflammatory processes  apoptosis, the faster
membrane disintegration one reacts to a stroke, the more cells remain in the oligemia-zone
 necrosis = can be saved!
Alzheimer’s dementia Cortical dementia (AD): impairment of higher cortical Diagnostics: detailed family history, psychopathology, Therapy: with drugs of symptomatic treatment: core symptom
(AD) functions, aphasia (speech and language disorder), memory neuropsychology, blood (cell count, renal and liver parameters, cognition (acetylcholinesterase-inhibitors, NMDA-receptor-
impairment, impairment of orientation, spatial dysfunction, inflammation, thyroid function, syphilis, vitamin B12, folate, antagonists), neuropsychiatric symptoms like delusion,
apraxia (disorder of motor planning, not caused by homocysteine), MRI (degeneration of hippocampus), EEG, depression, etc. (acetylcholinesterase-inhibitors, NMDA-
incoordination, sensory loss or failure to comprehend simple cerebrospinal fluid (cells, protein, Tau-protein, β-amyloid), receptor-antagonists, antidepressants, atypical neuroleptics,
commands, they just don’t know how to do something), agnosia: ultrasound of brain vessels, all to exclude any treatable cause for mood stabilizers, …); or causal treatment (in clinical trials but
inability to process sensory information, e.g. prosopagnosia dementia (~10%) not yet available!): disease modifying (amyloid β modifying
(recognizes face, but can’t make the connection to “this is my therapy, Tau modifying therapy, antioxidants, neuroprotective
daughter”), anosognosia (doesn’t realize he/she is ill), attention Neurocognitive assessment: neuropsychological testing is therapy, anti-inflammatory treatments, …)
declines, reduced ability to judge, reduced intellectual power, important for early diagnosis of dementia, severity of cognitive acetylcholinesterase-inhibitors: stabilizes the disease, mild to
physical assessment often normal in the earlier course impairment, differential diagnosis, exclusion of treatable causes, moderate stages
documentation of decline in repeated exams, documentation of Memantine: blocks NMDA-receptors, reduces “background
Progression: spared functions noise” caused by pathologically high Glu-release, learning signal
1st stage: mild cognitive impairment, evidence of memory can be transmitted again, improves memory
impairment, preservation of general cognitive and functional Dementia is a syndrome due to disease of the brain, usually of a Other therapy methods: cognitive therapy, occupational therapy
abilities, absence of diagnosed dementia chronic or progressive nature, in which there is disturbance of (Ergotherapie), physical activity, art therapy, sensory therapy,
2nd stage: mild AD, forgetfulness, short-term memory loss, multiple higher cortical functions including memory, thinking, family therapy (to help relatives deal with the illness)
repetitive questions, hobbies and interests lost, impaired orientation, comprehension, calculation, learning capacity, Survival of the patient depends mostly on age and cognitive
instrumental functions, anomia (loss of social skills) language and judgment, dementia is a psychological disorder, not performance at diagnosis
3rd stage: moderate AD, progression of cognitive deficits, neurological, the impairments of cognitive function are
aphasia, dysexecutive syndrome, impaired basic activities of daily commonly accompanied, and occasionally preceded, by Prevention: mental activity, genetics, physical activity,
living (BADL), transition in care deterioration in emotional control, social behavior or Mediterranean diet, moderate consumption of alcohol,
4th stage: severe AD, agitation, altered sleep patterns, total motivation, dementia occurs in AD, in cerebrovascular disease antioxidant drugs, antihypertensive therapy (against high blood
dependence: dressing, feeding, bathing, … after 8-9 years death and in other conditions primarily or secondarily affecting the pressure), non-steroidal anti-inflammatory rheumatics (NSAIRs)
brain, duration of symptoms is at least 6 months, there is
Neuropsychiatric symptoms: apathy, agitation, motor interference with activities of daily life
symptoms, depression, anxiety, irritability, delusion, disinhibition Classification: clinically (cortical, subcortical, frontal, etc.), Epidemiology: ~100’000 patients in CH have dementia, 24’700
(disregard for social conventions, impulsivity, and poor risk pathologically (degenerative, vascular, toxic, infectious, etc.), new diagnoses each year
assessment), hallucinations, euphoria stage (mild, moderate, severe) <65: very rare, cause by AD (34%), vascular dementia (18%),
other/unknown (14%), frontotemporal dementia (12%), alcohol
Risk factors: age, genetics, high blood pressure, diabetes, high Subcortical dementia: memory impairment, general slowdown, related (10%), Lewy body dementia (7%), Chorea Huntington
homocysteine levels, chronic stress, depression, traumatic brain impairment of attention, diffuse cognitive deficits (5%)
injury, obesity, cerebrovascular pathology ≥65: AD (56%), other/unknown (30%), vascular dementia
Frontal dementia: changes in character and affection, decrease (16%)
Pathophysiology: neurofibrillary tangles containing hyper- or increase of impulse, impairment of thinking (abstraction,
phosphorylated Tau-proteins, Tau binds microtubules and planning, judgement), memory impairment Etiology: neurodegenerative: most common cause for dementia,
regulates the structure of the cytoskeleton, amyloid plaques AD, PD, loss of neurons, vascular: 2nd most common cause,
containing amyloid-β-peptide (generated by β- or γ-secretase, stroke, inflammatory and infectious: syphilis, HIV, metabolic and toxic:
normal α-secretase doesn’t generate β-amyloid), clinical alcohol, drugs, traumatic brain injury, tumor, dementia mimic in mood
symptoms are more closely related to neurofibrillary tangles than disorders (e.g. depression)
to plaques
Brain tumors Epidemiology and pathology: primary and secondary brain Diagnosis: clinical: history: timing of symptoms onset and Therapy is only applied, if there is a chance for survival longer
tumors (originating from the CNS or metastasis, most common progression (stroke is usually faster than a tumor, symptom than the therapy lasts, usually at 70-80% on the Karnofsky scale,
are lung (40%), breast (20%) and skin cancer (10%), usually onset very recent and sudden, in brain tumors symptoms start below 30% therapy won’t help, between: decision dependent on
metastasize to the hemispheres (80%) followed by cerebellum sneaking in over time), physical examination; technical: imaging the patient
and brainstem with 15% and 5% respectively) (MRI, CT, X-ray, angiography, intraoperative imaging), nuclear
Secondary brain tumors are classified according to their origin medicine (positron emission tomography PET), lab Neurosurgery: goals: tissue sample for histopathological
tissue, primary brain tumors: neuro-epithelial, cranial / investigations (CSF), pathology (CSF, biopsy, resection), diagnosis, reduction / resection of the tumor, alleviation of a
paraspinal nerves, meninges, etc. molecular analysis, EEG mass effect, improving outcome, maximize surgical resection
Meningiomas: most frequent extra-axial tumor (53%), grades: while avoiding possibly devastating and permanent neurologic
I. 80%, benign, round, encapsulated, put pressure on CT/MRI: anatomical pictures ( pre-surgical planning) and complications, depending on histology: cure; indication: virtually
the brain, but don’t infiltrate the surrounding tissue, structural changes of the brain, contrast agent to reveal blood- always; extent of neurosurgery: stereotactic biopsy (cave:
operable, easily cured by surgery brain-barrier break down, perfusion MRI and spectroscopy sampling error), open biopsy, partial to complete resection; side
II. atypical might help to differentiate tumors from other causes for the effects: bleeding, infection, new neurological deficits, seizures,
III. anaplastic  II and III invade the brain, malignant symptoms or to obtain more information about the tumor type, CSF leakage, hydrocephalus; 5-ALA (Gliolan) causes red
Gliomas: most frequent intra-axial tumor, grades: fMRI might help the surgeon to calculate and avoid risks, helps fluorescence in tumor cells  helps in removing all tumor tissue
I. benign, curable, in children only during surgery, helps assess the tumor status after surgery,
II. cause epileptic seizures, no aggressive growth, puts monitoring tumor progression and treatment, helps in planning Radiotherapy: broad indication in all kinds of tumors, external
pressure on the brain, invasive  I and II are low external beam radiotherapy, intraoperative high-field MRI helps beam radiation (high-energy radiation: photons  X-ray or γ-
grade gliomas (LGG) in removing all of the tumor (time: +90min) ray, particles  protons), internal radiation (brachytherapy,
III. high grade gliomas (HGG) PET gives insight in tumor metabolism (fluoro-ethyl-tyrosine, iodine or iridium seeds or yttrium suspension), systemic
IV. Glioblastoma, 5 year survival <5%, median survival a FET, is metabolized by the tumor) or receptor status, Gallium- radiation therapy (Lutetium-DOTATE), treatment can be local
12-14 months DOTATE-PET: DOTATE binds to somatostatin receptors, (in gliomas), global (whole brain, when there is metastasis or a
which are found on the cell surface of a number of CNS-lymphoma) or cranio-spinal (neuro-axis, in medulla-
Symptoms: generalized symptoms: headache (only in 50% of neuroendocrine tumors and thus directs the radioactive Gallium blastoma, ependymoma, etc.), ionizing radiation (X-ray or γ-ray)
cases), balance, memory, apathy (from intracranial pressure), into the tumors, Lutetium-DOTATE tested for the treatment of causes direct and indirect damage (energy deposited in DNA,
neuro-cognition, epileptic seizures (focal or generalized), somatostatin-positive tumors radicals react with neighbouring molecules and produce
personality changes (easily missed!) Angiography might help for differential diagnosis and is useful for secondary DNA or lipid radicals), the full dose of radiotherapy is
Focal symptoms: motor, speech, vision, sensory the operation (diminishes operative time and intraoperative usually divided into fractions given over several weeks (unit:
There are no classical symptoms for brain tumors! Brain tumors blood loss) Gray, Gy: absorption of 1J of energy in the form of ionizing
can also cause stroke symptoms, because brain tumors invade CSF analysis can detect free swimming tumor cells radiation per kg of matter, 1Gy=1J/kg body tissue), standard for
the tissue, thereby destroying healthy tissue, and cause bleeding EEG helps detecting focal slowing, indicating a tumor glioblastoma: 30 x 2 Gy, on weekdays for 6 weeks, side effects:
and pressure headache, vomiting, hair loss, skin changes, wound healing
disturbance, neurocognitive changes, radiation necrosis (months
or years after radiotherapy, focal neurological symptoms, tumor
recurrence?)

Chemotherapy: alkylating agents (Nitrosourea CCNU,

Carbazine-group TMZ=temozolomide  only works in patients
with unmethylated MGMT promotor (2/3 of patients), Platins
Carboplatin), topoisomerase-inhibitors (/Etoposide), anti-
metabolites (MTX, in lymphomas), monoclonal antibodies
(Bevacizumab  doesn’t prolong the life of a patient, but
improves what’s left of it, Rituximab), experimental drugs in
clinical trial

Standard therapy in glioblastoma: surgery, radiotherapy, 4 weeks

break, MRI, chemotherapy with temozolomide  1st line
treatment, no standard for 2nd line yet, in case of recurrence:
another surgery, clinical trial group, another round of
chemotherapy, Avastin (starves the tumor), …
Autism Spectrum Disorders Qualitative impairment in reciprocal social interaction, Only behavioral symptoms, no biomarkers or measurable Treatment: 1 on 1 treatment at home or in the center, 25-35h
(ASD) qualitative impairment in verbal and nonverbal communication, changes weekly, students as therapists (otherwise it would be
restricted interest and repetitive patterns of behavior, onset Diagnostic tools: screening, interview, play observation unaffordable to most families), therapy lasts at least 2 years,
before age 2.5 year, sometimes unusual sensory interest, autism Suspicious symptoms during the 1st year of life: difficulties in based on Ivar Lovaa’s work  individual program for every
spectrum disorders include autistic disorder (early onset, mental parent-child interaction child and family, KOMPASS training program: recognizing
retardation, severely handicapped), atypical autism and Asperger Acoustic: little reaction to parents voice, no reaction to name emotions, expressing emotions, small talk, nonverbal
syndrome (normal to very high intelligence, normal language calling, very few preverbal sounds communication, group therapy for young adults and adolescents:
development, can lead a normal life  more stress than on Visual: missing or unusual eye contact, children with ASD look structuring relationship, social activities in public
autistic kids, because there is no special school for Asperger less at the eyes and more at the mouth or at objects, frequency
kids), also included but not discussed: childhood disintegrative of this behavior is indicative of how many autistic signs it will No medication yet, only for comorbid symptoms or disorders
disorder, Rett syndrome show at 24 months of age. During the first weeks there is no (hyperactivity, attention problems, aggressive or self-injuring
1/140 are autistic, thereof ¼ autistic disorder (30% with normal difference, but in ASD-children eye contact will decrease  lack behavior, depression, anxiety, compulsive behavior, sleep
IQ, 70% with IQ below 70), ½ atypical autism and ¼ Asperger, of reinforcement? disorders)
overall 55% have a normal IQ Tactile: unusual reaction to touch or body contact
Autism seems to be more common in certain places, due to Healthy children will show a steady increase in directed social
genetics or because of preferences of autistic people (like and interactive behavior between 6 and 12 months of age,
computer works  prevalence higher in silicon valley and whereas children with ASD show very little or no increase and in Asperger in girls: same pattern, less severe expression, less
similar places) some instances even a loss of these behaviors disruptive, often undetected, coping mechanisms: hiding and
Influences: more prevalent in boys than in girls (as with most Suspicious symptoms during the 2nd year of life: delay in speech mimicking, imitation, doll play peer support, reading, best girl
developmental disorders), mental retardation, epilepsy, multi- development/communication, no sharing of the world with friend
case families, associated with neurological disorders (Tuberous others (joint attention: pointing at interesting objects, bringing Special interests, imaginary friends; girls tend to not disturb
sclerosis, fragile-X-syndrome), extreme prematurity (early born objects in order to show them, looking at parents face for social other people the way boys do, also they blame themselves
children), age of parents (3x increase when mother is >35 and clues, joint looking at pictures), lack of imitative play, very little instead of others, asking “what’s wrong with me?” whereas
father >40 for the 1st born child, 2nd usually less affected), or unusual nonverbal communication, loss of verbal or social autistic boys wonder “what’s wrong with everybody else?”
migration of parents, medication during pregnancy (medication abilities
against epilepsy), infection during pregnancy (e.g. rubella), Suspicious symptoms after age 2: little interest in other children, Savants: 50% of Savants have ASD, the other 50% have other
environmental influences during pregnancy (chemicals, missing or unusual language, repetitive and restrictive play neurological symptoms, but only about 10% of autistic people
pollution), folic acid behavior, little interest in picture books or stories, fascination for are Savants, more common in boys than in girls
rotating or glittering objects, unusual hand or body movements,
Neuropsychology: no complete model for autism yet, social hyper- or hypo-sensitivity to sounds, smells or touch Musicians with perfect pitch have autistic signs, are more
motivation hypothesis, theory of mind, weak central coherence, eccentric, but they also have lesser social abilities (eccentric and
intense world model Diagnostic criteria: difficulties with reciprocal social interaction autistic are very close)
The social motivation hypothesis: reduced social interest  lack of (extreme egocentricity), restricted interests, routines and rituals,
social experiences  reduced social learning and less options of speech and language difficulties, difficulties with nonverbal Problems in daily life: difficulty interpreting facial expressions
adequate cognitive learning communication, clumsiness and situations, problems finding friends, often they’re bullied,
Theory of mind: ability to think about other people’s thoughts, to don’t stick to unwritten laws and rules, make insulting remarks
realize that other people have other thoughts, wishes and Strong central coherence: rapid focus on the complete picture, global (out of honesty), talk only about their favorite subjects, spend a
motives than their own, and to take other people’s perspectives, information processing, integrating different information to lot of time (and money) for their special interest, stick to their
theory of mind is a precondition for empathy understand a situation, central coherence is the ability to routines and find changes in their activities very difficult, their
Sally and Ann-Task: more difficult for autistic kids even in combine different elements to create a picture and to neglect motor coordination is weak, often show sensory problems with
comparison with other mentally retarded kids details, memorize a message not literally, but to remember the noise, light and smell, hate surprises and unexpected events,
Intense world theory: sensory overload, like moving from a dark and meaning problems functioning in groups
quiet cave to a loud disco with stroboscopic lights and masses of Weak central coherence: local information processing, ability to
people, options: reducing sensory input by retiring to a quiet focus and recognise details immediately, preference to occupy Upsides of being an Asperger: extremely reliable and loyal,
room, minimizing surprises by following routines, searching for oneself with details and memorizing words and sentences of a honest, communicate without second thoughts or double
patterns and structures message but not the meaning  ASD-kids are better at the meaning, highly original problem solvers, incredible memory for
Adults can flee from sensory overload, babies have to block out embedded figures task details, extraordinary knowledge in their special field
sensory stimuli and reduce communication and interaction, Concretism: difficulty to understand irony, jokes, proverbs, double
research shows, that the resting brain of ASD-people might meaning, etc., sensory overload is often underestimated
process more information than the brain of neuro-typical people
Schizophrenia Schizophrenia is a severe mental disorder characterized by No biomarkers for diagnosis, only clinical assessment, blood Therapy (social, psychological and biomedical):
profound disruptions in thinking affecting language, perception tests, CSF, imaging (MRI), EEG, neurocognitive assessment ( antipsychotic agents (pharmacotherapy), psychotherapy:
and the sense of self. It often includes psychotic experiences most of them for differential diagnosis, to rule out dementia or psychoeducation aims to empower people suffering from
such as hearing voices or delusions. It can impair functioning other neurological diseases) schizophrenia by giving them information and knowledge about
through the loss of an acquired capability to earn a livelihood or their illness, individual therapy helps to develop strategies to
the disruption of studies. ICD-10: to diagnose schizophrenia, either at least one of the better deal with symptoms, cope with stress and identify early
syndromes, symptoms and signs from I or at least two from II warning signs of relapse, social therapy: social skills training
Hallucinations: perception-like experiences that occur without should be present for most of the time during an episode of focuses on improving communication and social interactions,
an external stimulus and that are not under voluntary control, psychotic illness lasting for at least one month (or at some time family therapy provides support and education to families
may occur in any sensory modality, can be vivid and clear with during most of the days) dealing with schizophrenia, vocational rehabilitation and
the full force and impact of normal perceptions, auditory Most commonly used exclusion criteria: if the patient also meets supported employment focuses on helping people with
hallucinations are usually experienced as voices, whether familiar criteria for manic or depressive episode, the criteria from I and schizophrenia to prepare for, find and keep a job, supported
or unfamiliar, that are perceived as distinct from the individual’s II must have been met before the disturbance of mood housing
own thoughts, must occur in the context of a clear sensorium, developed. The disorder is not attributed to organic brain disease
those that occur while falling asleep (hypnogogic) or waking up or to alcohol or drug related intoxication, dependence or Negative symptoms: reduction in normal functions, affective
(hypnopompic) are considered to be within the range of normal withdrawal flattening (reductions of facial expression, eye contact,
experience I intonation of speech and movements of hands, head and face
 Thought echo, thought insertion or withdrawal, thought that normally give an emotional emphasis to speech), anhedonia
Delusions: fixed beliefs that are not amendable to change in broadcasting (decreased ability to experience pleasure from positive stimuli),
light of conflicting evidence, persecutory (unjustified belief that  Delusions of control, influence or passivity, clearly referred apathy/avolition (decrease in motivated self-initiated purposeful
one is going to be harmed), referential (unjustified belief that to body or limb movements or specific thoughts, actions activities), alogia (diminished speech output), asociality/social
certain gestures, comments, environmental cues etc. are directed or sensations; delusional perception withdrawal (apparent lack of interest in social interactions)
at oneself), grandiose (unjustified belief that one has exceptional  Hallucinatory voices giving a running commentary on the
abilities, wealth or fame), erotomanic (unjustified belief that patient’s behavior or discussing him between themselves Catatonia: grossly abnormal behavior marked by an excess or
another person is in love with him/her), delusional perception or other types of hallucinatory voices coming from some lack of motor activity in reaction to one’s environment,
(real perception that is falsely interpreted and charged with part of the body negativism (opposition or no response to instructions or external
meaning in the light of a delusional belief, e.g. seeing helicopters stimuli), mutism (no or very little verbal response), muscular
 Persistent delusions of other kinds that are culturally
and thinking the 3rd world war has broken out), delusional mood rigidity and waxy flexibility (allow positioning by examiner and
inappropriate and completely impossible (e.g. being able to
(unjustified, diffuse expectation that something is wrong or maintain position), stupor (no psychomotor activity, not actively
control the weather or being in communication with aliens
something bad is going to happen, uncanny feeling) relating to environment), agitation (excessive excitability and
from another world)
motor activity), stereotypy (repetitive, abnormally frequent, non-
II
Ego-disturbances (Ich-Störung): weakening or loss of the goal-directed movements)
 Persistent hallucinations in any modality, when occurring
ability to distinguish between self and other, thought insertion
every day for at least one month, when accompanied by
(feeling that one’s thoughts are one’s own), thought withdrawal Cognitive impairments: found in almost all patients, precede
delusions (which may be fleeting or half-formed) without
(feeling that one’s thoughts are taken away  can result in the onset of psychosis, are not caused by psychotic symptoms,
clear affective content or when accompanied by persistent
abrupt stop during speech or at least that’s how it feels to the are important for functional disability and outcome
over-valued ideas
patient), thought broadcasting (feeling that one’s thoughts are
audible to others  patient prefers to read while alone in order  Neologisms, breaks or interpolations in the train of Genetic variants: >100 genetic loci with fairly common SNPs,
to not disturb anyone around him/her), delusion of control thought, resulting in incoherence or irrelevant speech 11 rare CNVs, rare SNPs and indels (inherited and de novo),
(feeling that one’s motor actions are controlled by an external  Catatonic behavior such as excitement, posturing or waxy most code for synaptic proteins (e.g. post-synaptic density
agent) flexibility (put patient into a certain posture, patient then protein, dysbindin and neuregulin), ion channels (e.g. voltage-
stays like this), negativism, mutism and stupor dependent Ca-channels), receptors (e.g. Glu- and Dopamine
Formal thought disorder: disturbance of the ability to generate  Negative symptoms such as marked apathy, paucity of receptors), enzymes involved in neurotransmission (e.g.
a logical sequence of ideas (train of thought) typically speech and blunting or incongruity of emotional responses monoamine oxidase A), major histocompatibility complex
manifesting in an individual’s speech, rumination (tendency to (it must be clear that these are not due to depression or to (MHC), all observed variants are pleiotropic: overlaps with other
think repetitively about unpleasant, distressful topics), neuroleptic medication) mental disorders like bipolar disorder, major depressive disorder,
circumstantiality (long-winded, convoluted speech), tangentiality ADHS and autism spectrum disorders
(replies to questions are off-point or irrelevant), loosening of Differential Diagnosis: somatic disorders: inflammatory brain
associations and derailment (total break in the chain of disease (MS, encephalitis), traumatic brain injury (head injury, Disturbances in dopaminergic neurotransmission: 5
association between meanings of thoughts), neologisms (making stroke), epilepsy, autoimmune diseases (Lupus erythematodes), dopamine pathways in the brain: nigro-stratial, meso-limbic,
 up new (compound) words), flight of ideas (subjective metabolic conditions (M. Wilson), substance induced psychosis; meso-cortical ( important in schizophrenia), tubero-
experience of being under pressure from an excess of different other mental disorders: acute transient psychotic disorders, infundibular, projections from multiple sites to the thalamus
ideas and thoughts), thought blocking (subjective experience of delusional disorder, schizoaffective disorder, mania or
the sudden and unintentional stop in a chain of thought, often depression with psychotic symptoms Risk factors: family history (monozygotic twins, parents,
associated with thought withdrawal), incoherence (severe dizygotic twins or 1st degree relative, 2nd and 3rd degree relatives),
disorganisation that makes speech incomprehensible, word Epidemiology: overall prevalence 1%, prevalence for individual genetics, urbanity, migration, 1st or 2nd trimester maternal
salad) psychotic symptoms is much higher infection or malnutrition, winter birth, obstetric and perinatal
complications, cannabis or stimulant use, smoking, paternal age
Cause: vulnerability stress model: everyone can develop Mortality: 5-10% die by suicide, ~50% attempt it, somatic >35, male gender, daylight influence (prevalence is higher in
schizophrenia (or more general: a psychosis) if the “right” illnesses due to unhealthy lifestyle, suboptimal treatment of northern countries), general trend: 80% of people with psychosis
circumstances are given, but some people can endure more physical disorders, side effects of psychotropic medication tend to conduct an unhealthy lifestyle (smoking, drinking,
stress than others; etiological hypothesis overweight, …)
Outcome (general rule): 1/3 good remission, 1/3 partial
remission, 1/3 chronic

Diagnostic procedures
Problems in clinical neuroscience From symptoms to disease to pathophysiological mechanism: Symptoms (weakness, blurred vision, vertigo, memory failure, headache…) – diagnostic procedure, differential diagnosis: specific disease, syndrome
(=characteristic group of symptoms) – underlying neurobiology and pathological processes

 Improve diagnostic tools

 model of a disease should be comprehensive
 frequent mismatch between clinical importance of a disease or syndrom and its visibility in the scientific community (e.g. high visibility for genetic neurodegeneration, poor recognition of chronic pain, headache, sleep disturbances…)
Many diseases show a spectrum of manifestations - One or several different diseases? (e.g. schizophrenia, autism, multiple sclerosis…)
 Multifactorial background of age, sex, environmental conditions, life style…(search for causative factors!) - Genetic vs. environmental factors - challenge for disease classification - challenge for the appropriate modelling of the disease
Mechanistic analysis, experimental approach in animal models Model must match (as many as possible, ideally all!) the central characteristics of the disease Model must be accessible for experimental manipulations and analytical dissection
(fish/fly > rodents > higher mammals) - Goal are hypotheses on the pathophysiological mechanism of a specific disease or disease condition - Derived from these mechanistic insights: Novel experimental therapies (to stop and reverse
the disease, repair damage, compensate lost functions)

New therapies: From animal models to clinical application, defined stages:

 Preclinical evaluation: Proof of concept in >1 animal species with relevance to man, efficacy, mechanistic insights, - absence of negative effects or toxicity. – Patenting
 Development: Large scale production under GMP conditions of clinical grade substances; formulation and route of application; developments of devices for easy general practise
 Clinical trial Phase 1: Dosage and way of application, tolerability and safety: absence of side effects and toxicity; open-label (no controls), observation of effects in comparison with historical controls
 Clinical trial Phase 2: Efficacy, proof of concept in man. Double-blind, randomized with controls. Small numbers of test subjects, few sites.
 Clinical trial Phase 3: Multicentric, multinational, large numbers of patients (very high costs: hospital days, follow-ups, insurance, administrative costs for patents, regulatory authorities)
 If successful: Drug or device admitted, recommended use

Neuro-Rehabilitation
Physical trauma: immediate destruction of tissue, mostly due to bone splitters  necrotic death within 1-60 min, followed by secondary degenerative events due to different mechanisms (after 30 min - days): ischemia in surrounding tissue due to
microthrombosis of blood vessels: slow ischemic death of neurons, often by apoptosis (research: prevent apoptosis to save tissue), release of neurotransmitters from ischemic terminals: high levels of glutamate lead to over-excitation of neurons
and toxic intracellular Ca-concentrations (excitotoxicity,  research: glu-receptor inhibitors, not very promising yet…), free radical formation (catalyzed by iron from bleedings) causes lipid peroxidation and membrane damage, inflammation
triggered by tissue damage, myelin damage, demyelination of intact fibers  functional damage, pressure damage by edema  swelling in myelin, temporary block of conduction. Late phase: Scar formation (by astrocytes, microglia/macrophages
and meningeal fibroblasts) and cyst formation (filled with cerebrospinal fluid)  decreases or inhibits conductivity

Stroke, ischemic lesion: Fast necrotic tissue death in the center of the lesion due to iron, followed by slower degenerative processes in the surrounding penumbra (Schattenregion), very similar to mechanical trauma. Late phase: fluid-filled holes,
surrounded by scar tissue
Functional consequences of the lesion: immediate loss of functionality in fiber tracts and circuits: paraplegia (thoracic or lumbar spinal cord injury, legs and lower body), tetraplegia (cervical spinal cord injury, upper and lower extremities),
hemiplegia / hemiparesis (impairment of one side of the body after stroke or unilateral spinal cord injury), lesion above C5 will lead to inability to breathe, 10-20% of stroke patients can be saved with thrombolysis if it’s applied within 4 hours after
the incident, 1-6 months after incomplete spinal cord injuries or smaller strokes gradual, often partial recovery of certain functions, mechanism still under investigation, clinical therapeutic approach: rehabilitative training

Mechanisms of structural and functional repair after CNS-trauma:

 Regenerative sprouting and elongation of injured axons, formation of relay circuits, many CNS axons react to injuries by a transitory regeneration attempt, these sprouts can connect to targets proximate to the lesion: e.g. hind limb
motor cortex axon collaterals connect to cervical spinal cord and assume forelimb functions. They can also contact spared propriospinal neurons that bridge the lesion and form a relay pathway, regeneration can be stimulated by applying
antibodies against growth inhibitors (Nogo-A, growth factors)
 Compensatory sprouting of intact spared fibers, functional map shifts, intact fibers sprout and take over targets that have lost their input, the neurons of origin have to change and adapt their input connection to form a new functional
circuit: e.g. after small stroke lesions, neighbouring parts of the motor cortex assume control over body parts that have lost their input  remapping of the motor cortex
 Myelin-repair: new neurons or new oligodendrocytes, proliferation of stem cells is frequently observed in regions surrounding the trauma site, but no new neurons are formed. New astrocytes contribute to the scar tissue and ~10% of
the cells differentiate into oligodendrocytes which can form new myelin

Rehabilitative training: intense, repetitive training in rats induces strengthening of pre-existing connections spared by the lesion (potentiation of synapses), stabilization of newly formed connections, selection of functionally meaningful
connections out of randomly formed circuits, pruning (destabilisation) and elimination of malfunctioning connections and induction of growth, possibly via upregulation of growth factors

Recovery after stroke: assisting adaptation (compensation) vs. reducing impairments (true recovery), both mechanisms can ultimately lead to independence of the patient

Fugl-Meyer score at 24 to 72 hours after the stroke predicts recovery after 3 to 6 months: if a patient still reaches more than 20/66 points the will regain ~70 of their pre-stroke score, if the patient is below 20 points recovery is very unrealistic

In severely impaired patients a more widespread, bilateral activation is seen on the MRI and they show post treatment increases in the contralateral motor regions and shifts in laterality, whereas more normal activation patterns in mildly impaired
patients are seen. Emerging evidence supports functional relevance of secondary motor area recruitment.

According to estimates patients would need up to 10 times more therapy during the rehabilitative phase, can’t be provided due to costs and limited personnel, BUT conventional neurorehabilitation appears to have little impact on impairment,
constraint induced movement therapy is the only scientifically proven method, restraint of the less affected extremity for 90% of waking hours, massed practice with affected limb for 6 hours a day using shaping, overcome learned non-use,
frustrating as it only works in patients with remaining motor function  these patients would recover 70% of their abilities on their own (probably not as fast, but still…), also criticized: may train compensatory strategies instead of true recovery

Novel therapeutic approaches:

 technology based assessments to gain a better understanding of response to specific treatments and transfer to the home environment: objective, sensitive and rapidly administered, e.g. virtual reality and robotics, wearable sensory for
long-term activity at home
 robot assisted rehabilitation: complement conventional therapy, increase in duration and intensity, patient tailored therapy, robot adapts and compensates just enough for the patient to benefit from the training, strengthening of muscles
through functional electrical stimulation, possibility of group therapy
 neural stimulation: transcranial magnetic brain stimulation, transcranial direct / alternating current stimulation, transcranial random noise stimulation, brain machine interfaces  going the opposite way: not training muscles to form and
stabilize neurons and circuits, but form functional neurons by stimulating them directly in the brain

Conclusions: there is only limited understanding of mechanisms underlying sensorimotor control and recovery, lack of tools to improve understanding, principles of motor learning must be applied to develop new therapies: treatment of both motor
and sensory aspects (in conventional therapies sensory inputs are not treated at all), interaction dynamics (forward models), include the brain in the loop, provide high intensity, repetition and variability, promote close collaboration between
scientists, clinicians and engineers

Planning clinical trials

Clinical Trials Center: support of researchers with services and education, main field: investigator initiated trials, Phase I unit (only for small studies or if special equipment is needed, most trials are conducted in hospitals), study investigators and
study coordinators, services in regulatory affairs, monitoring, data management, support of inspections and audits, set up and maintenance of quality management system, clinical research training and education programs, USZ study registry

Partner organisations: Epidemiology, Biostatistics and Prevention Institute, Unitectra  technology transfer and contracts, Rechtsdienst  legal issues and contracts, IMP  cantonal pharmacy Zürich, University Center for Laboratory Medicine,
Clinic for Pharmacology and Toxicology USZ, and other national and international collaborations  ICN (International Clinical Trial Center Network)

Clinical Trials: no difference between sponsored clinical research and investigator initiated research, industry as sponsors, investigator initiated trials, non-commercial trials, epidemiological / observational trials (non-interventional trials), trials for
medical devices, clinical trials in other areas (surgery techniques, a. o.)

Phase I: toxicity, safety, tolerability, metabolism, on healthy volunteers, sometimes healthy symptomatic volunteers, 10-50 participants,  safe dosage, treatment administration, effects on the body
Phase II: therapeutic exploration, proof of concept, dose optimizing, side effects, 50-200 patients, tested against control group with either standard line treatment (if one exists) or against placebo,  does the treatment work, does it affect the body?

Phase III: therapeutic confirmation, efficacy, statistical significance  200-1000+ patients, risk / benefit, dose optimising, reality conditions, control groups, start marketing and contracts with industry

Phase IV: post marketing authorisation, after medical product is approved by health authorities, long-term safety, efficacy, testing of subgroups (pregnant women, children, elderly, etc.)

Complete process takes ~10 years and 100 Mio. CHF! The previous phases are always tested, no matter in which phase the trial is, toxicity and side effects may appear only in very large groups of test subjects or only after several years.

Different types of clinical trials: treatment, prevention, screening and early detection, diagnostic, genetics, quality of life, supportive care

Regulations in different countries:

USA: FDA (food and drug administration), belongs to the department of health and human services, CDER (center for drug evaluation and research), application for a clinical trial via institutional review board, only with investigational new drug
applicant form (IND) and NDA (new drug application)

EU: EMA (European agency for the evaluation of medicinal products), CPMP (committee for proprietary medicinal products / scientific committee for medicines for human use)  guidelines and notes for guidance

CH: swissmedic, strictest laws on clinical trials  human research act (HRA), KlinV: clinical trials and health related intervention, HFV: non-clinical trials, personal data and biological material, risk categorisation: A: low risk, test object is
swissmedic approved, use according to prescribing information, deviation from prescribing information according to predefined criteria, approval by ethical committee*, simplified submission document, simplified safety reporting, reduced
indemnification (Sicherstellung) obligation, B: medium risk, test object swissmedic approved, deviation from prescribing information outside of predefined criteria (use for different indication, different dosage, drug on the market in Europe or
America, …), approval by ethical committee and swissmedic*, simplified submission document, simplified safety reporting, C: high risk, for completely new inventions or procedures, approval by ethical committee and swissmedic*

*approval needed for all research projects on humans and reuse of biological specimens and health related personal data, new: parallel submission possible

Swissmedic: quality and safety, requirements according to current directives, risks, product performance

Ethical committee: risk/benefit ratio, efficacy, ethical issues, participants’ information and rights  good clinical practice, lead ethical committee: in charge at the coordinating investigator’s location, involved ethical committees: concerned with
professional and institutional prerequisites of the involved investigators / external centers in other Cantons

Transparency is important: public register of clinical trials  WHO, clinicaltrials.org, Swiss national clinical trial portal

ICH: international conference on harmonisation, working group of pharmaceutical industry experts and regulatory authorities from USA, EU and Japan, goal: produce a single set of technical requirements for the registration of new drugs to
streamline preclinical and clinical development, remove redundancy / duplication in drug development and review processes, more economical use of human, animal and material resources,  a single set of data should demonstrate safety, quality
and efficacy of the new drug

Safety: relating to in vitro and in vivo preclinical studies; Quality: relating to chemical and pharmaceutical quality assurance; Efficacy: relating to clinical studies in human subjects  good clinical practice (GCP, E6); Multidisciplinary topics: topics
that don’t fit into one of the above categories

GCP: international ethical and scientific quality standard for designing, conducting, recording and reporting of clinical trials that involve human subjects, design standards: protocol and investigators brochure content, project is scientifically sound
and feasible, adequate resources (research personnel), randomization and blinding procedures, conduct standards: regulatory and ethics committee approval, compliances with protocol (anything off protocol needs extra approval), informed consent,
confidentiality, medical management, adverse event recording, qualifications and training, recording standards: case report form completion, data handling / management, security, audit trails (who did what), product accountability (drug count),
study files, essential documents, reporting standards: safety reporting (serious adverse events), progress reports, monitoring reports, audit reports, clinical trial report,  regulate authorities, ethics committees, sponsors and investigators, primary
objective: safeguard the rights and interests of research subjects

GCP: official definition: GCP is an international ethical and scientific quality standard for designing, conducting, recording and reporting trials that involve the participation of human subjects, compliance with this standard provides public assurance
that the rights, safety and well-being of trial subjects are protected, consistent with the principles of the declaration of Helsinki and that the clinical trial data are credible.

Before GCP: Dr. Massengill’s Elixir, contained anti frost as solvent, misuse of prisoners in WWII, Tuskegee study on syphilis, Thalidomide (Contergan) leading to deformed children, even today tragedies and scandals can happen, but at least a lot
less often and not as easy as before.