Ataxia & Cerebellar Disease

Question 1

Anatomic causes of ataxia

Answer 1

1) cerebellum and its connecting pathways
2) malfunction of sensory input from proprioceptive sensory pathways or the vestibular system into the cerebellum

Question 2

Distinguishing features of cerebellar ataxia and 1) sensory ataxia 2) labyrinthine ataxia

Answer 2

1) With proprioceptive ataxia, incoordination often
increases dramatically when the patient’s eyes are closed.
Oculomotor symptoms such as nystagmus point away from sensory ataxia.

2) Patients with labyrinthine ataxia also have impaired gait and balance, but speech is not affected and limb movements are coordinated

Question 3

Functional division of cerebellum

Answer 3

For the purposes of clinical localization, it is useful to distinguish between the midline cerebellum and the cerebellar hemispheres.
Cerebellar syndromes can be divided into symptoms arising from one or the other, although there is significant clinical overlap

Midline cerebellar structures include the vermis (σκώληκας), the fastigial (οροφιαίος) and interposed globus (σφαιροειδής) and emboliform (εμβολοειδής) nuclei, the vestibulocerebellum (flocculus (κροκύδα) and nodulus (οζίδιο), and the paravermis/intermediate zone.

The right and left cerebellar hemispheres include the dentate (οδοντωτός) nuclei on each side.

Question 4

Midline cerebellar dysfunction syndrome

Answer 4

● Imbalance – Patients tend to fall when standing with their feet together, whether their eyes are opened or closed. They may adopt a compensatory wide-based stance. They often have difficulties with gait, especially tandem walking. They may complain of a sensation of disequilibrium.

● Truncal ataxia
(Patients can also have bilateral upper limb ataxia, as seen in hemispheric dysfunction, especially if the paravermis/ intermediate zone region of the cerebellum is damaged)

● Titubation (έντονος τρόμος κεφαλής) – Titubation is an involuntary, semirhythmic nodding of the head, neck, and/or trunk that is often seen with midline cerebellar dysfunction.

● Lower-limb dysmetria

● Saccadic intrusions – Saccadic intrusions are the most common ocular abnormality caused by midline lesions. Intrusions are irregular bursts of rapid eye movements that include opsoclonus, ocular flutter, square wave jerks (αδυναμία προσήλωσης), and macrosaccadic oscillations. They are often but not always a sign of midline cerebellar pathology.

● Nystagmus – Horizontal gaze-evoked nystagmus is commonly seen with midline cerebellar injury. Often the nystagmus is more prominent when looking towards the side of the lesion, although nystagmus in all directions of gaze is usually present

“Ocular dysmetria” is the term applied to hypermetric saccadic eye movements. After overshooting, the eyes rapidly correct their position to focus appropriately on the object in question. This finding is very suggestive of cerebellar dysfunction.

● Vertigo – Vertigo with nausea and vomiting may result from damage to the vestibulocerebellum and is usually associated with saccadic intrusions and nystagmus.

Question 5

Hemispheric cerebellar dysfunction syndrome

Answer 5

The cerebellar hemispheres are largely responsible for motor planning and coordination of complex tasks.
Damage to one hemisphere leads to symptoms that are most notable in the ipsilateral limbs.
Clinical signs of hemispheric cerebellar dysfunction include:

● Dysdiadochokinesis

● Dysmetria

● Limb ataxia

● Intention tremor

● Ataxic dysarthria – Ataxic dysarthria is characterized by alternating loudness and fluctuating pitch levels, such that the emphasis is placed on syllables that should not be stressed. It can also manifest as scanning speech, which refers to slow enunciation with pauses in between syllables and words. Patients can also exhibit irregular articulatory breakdown, transient nasality, harshness, or breathiness.

● Ocular findings – Ocular findings are generally less prominent, but broken smooth pursuits and ipsilateral gaze-evoked nystagmus are often seen.

Question 6

Common causes of a midline cerebellar syndrome

Answer 6

alcoholic cerebellar degeneration and medulloblastoma

(Alcohol preferentially poisons the vermis, leading to a characteristic syndrome of gait ataxia with sparing of the limbs)

Question 7

Common causes of a cerebellar hemispheric syndrome

Answer 7

• cerebellar astrocytoma
• multiple sclerosis
• lateral medullary stroke

Question 8

Down-beating, up-beating and rebound nystagmus localization

Answer 8

Down-beating present in primary gaze or induced by up-gaze localizes to the cerebellar flocculus, as does rebound nystagmus, which is the induction of nystagmus upon return to primary gaze.
Both of these can be seen in other processes

Up-beating nystagmus can be seen with midline cerebellar vermis lesions as well as in brainstem lesions

Question 9

Causes of ataxia
Acute, subacute and chronic

Answer 9

Question 10

Causes of ataxia
Acute, subacute and chronic

Answer 10

διημερίδα Ιανουάριος 22’

Question 11

Evaluation of subacute/ chronic ataxia

Answer 11

https://www.uptodate.com/contents/image?imageKey=NEURO%2F129765&topicKey=NEURO%2F14134&search=ataxia&rank=1~150&source=see_link

Question 12

Treatable ataxias

Answer 12

Treatable ataxias include:
1) abetalipoproteinemia
2) ataxia with isolated vitamin E deficiency
3) Other vitamin deficiencies (B12, Copper)
4) cerebrotendinous xanthomatosis
5) Wilson disease
6) Niemann Pick type C
7) autoimmune ataxias
i) hashimoto thyroiditis
ii) sarcoidosis
iii) cerebellar ataxia associated with antibodies against cerebellar antigens (eg, GAD65, P/Q calcium channel, and voltage-gated potassium channels [VGKCs], including contactin-associated protein-like 2 [Caspr2]) may be negative for occult malignancy.
These disorders can respond to intravenous immune globulin (IVIG), plasma exchange, or oral immunosuppressants
iv) MS
v) PML
vi) ADEM
vii) Miller Fischer
8) Acquired hepatocerebral degeneration
9) Hypoparathyroidism
10) Hypothyroidism
11) hereditary motor and sensory neuropathy IV (Refsum disease)

Question 13

Clinical findings in infarction of the posterior
inferior, superior, and anterior inferior cerebellar arteries

Answer 13

Question 14

Cerebellar ischemic stroke treatment

Answer 14

As any ischemic stroke

+ infarcts >2.5cm intensive monitoring for edema and brainstem compression or obstructive hydrocephalus

Question 15

Medications and toxins that cause ataxia

Answer 15

Antiseizure medications –
especially those that affect sodium channel conductance such as phenytoin, carbamazepine, oxcarbazepine, lacosamide, lamotrigine, rufinamide, and zonisamide.
Ataxia is also seen with benzodiazepines, felbamate, phenobarbital, and valproic acid in the setting of hyperammonemia

Effects are usually reversible when the medicine is stopped, but chronic administration of phenytoin in particular can lead to permanent cerebellar degeneration.

Chemotherapy –
Chemotherapy can be associated with both reversible and permanent cerebellar ataxia.
Cytarabine, often used in treatment of leukemias and lymphomas, and fluorouracil, which is used in various cancer treatments including colon cancer therapy, are the most common chemotherapeutics associated with acute cerebellar ataxia.

Others –
Additional chemotherapeutic agents that may be associated with acute cerebellar ataxia include capecitabine, hexamethylmelamine, procarbazine, vincristine, and other vinca alkaloids.
As a separate issue, certain chemotherapeutic agents, including cisplatin and oxaliplatin, are associated with the development of sensory ataxia caused by neurotoxicity affecting dorsal root ganglia and peripheral nerves.

Toxins and poisons –
Toxins and poisons associated with cerebellar ataxia include alcohol, carbon tetrachloride, heavy metals, phencyclidine, and toluene
Perhaps the most common cause of acute-onset cerebellar ataxia is excessive alcohol ingestion, which usually produces a midline cerebellar syndrome, characterized by ataxia of legs and gait with relative sparing of the arms

Question 16

Percentage of patients with celiac disease and neurologic symptoms

Answer 16

6-10%

Question 17

Gluten ataxia clinical findings

Answer 17

• Progressive gait and limb ataxia, and sometimes
  dysarthria, abnormal eye movements, pyramidal signs,
  and memory decline.
• Some have myoclonus and palatal tremor

Gastrointestinal complaints 10%

Associated conditions sometimes include osteoporosis, dermatitis herpetiformis, autoimmune thyroiditis, and diabetes mellitus
There is increased risk of lymphoma

Question 18

Gluten ataxia laboratory findings

Answer 18

IgA anti-tissue transglutaminase (tTG) antibody is the single preferred test for detection of celiac disease in adults.
In addition, we concurrently measure total IgA levels.
In patients with IgA deficiency we perform IgG-based testing with deamidated gliadin peptide (DGP) IgG.

Also elevations in
1) antigliadin (IgA and IgG)
2) antiendomysial (IgA)

Anti-GAD autoantibodies and antiganglioside antibodies have also been detected.

There may be vitamin deficiency, including folate, vitamin K, and vitamin D; iron-deficiency anemia; and elevated liver enzymes.

Question 19

Gluten ataxia age of onset

Answer 19

Typically affects individuals older than 50 years

(cases in younger people, including pediatric patients, have been reported)

Question 20

Gluten ataxia imaging and treatment

Answer 20

MRI often reveals cerebellar atrophy, sometimes limited to the vermis and sometimes pancerebellar

(>60%)

Improvement sometimes follows implementation of a glutenfree diet and repletion of nutritional deficiencies

Question 21

Diagnostic testing for suspected vitamin B12 or folate deficiency

Answer 21

Question 22

Postinfectious cerebellitis

Answer 22

a condition classically seen between one and six weeks after varicella or measles infections in children but can also occur after Epstein-Barr or other viral infections and vaccinations in teenagers and young adults

Brain MRI studies may be normal or can demonstrate diffusion and T2-weighted cerebellar hemispheric abnormalities

Postinfectious cerebellitis is usually a monophasic illness that has complete resolution regardless of treatment, but it can be complicated by cerebellar edema requiring interventions such as glucocorticoid treatment, surgical decompression, or ventriculoperitoneal shunting for hydrocephalus

Question 23

Paraneoplastic syndromes producing ataxia and cerebellar degeneration

Answer 23

Question 24

Paraneoplastic cerebellar degeneration: most frequent causes

Answer 24

lung cancer (particularly small cell lung cancer)
gynecologic cancer
breast cancer
and lymphoma (mainly Hodgkin disease)

The neurologic symptoms frequently precede or coincide with the diagnosis of cancer.

Question 25

Mixed sensory and cerebellar ataxia causes

Answer 25

Question 26

Late onset genetic ataxia syndromes

Answer 26

Question 27

Approach of genetic testing in ataxia

Answer 27

Our approach for patients with a slowly progressive cerebellar ataxia of unknown etiology is as follows:

● We screen all patients for the most common inherited causes of cerebellar ataxia that result from nucleotide repeat expansions.
Specifically, we evaluate for SCA types 1, 2, 3, 6, 7, and 8, Friedreich ataxia, and replication factor C subunit 1 (RFC1)-related ataxia, regardless of family history ++ SCA27b!
In patients with pigmentary retinopathy, we start testing with SCA7.

The yield of this limited genetic testing in patients with ataxia who have been prescreened for secondary causes is approximately 10 percent

● If first-line testing is unrevealing, we test older males for fragile X messenger ribonucleoprotein 1 (FMR1) gene premutations associated with fragile X-associated tremor/ataxia syndrome (FXTAS).

● In remaining cases of cerebellar ataxia with a chronic progressive course and no confirmed etiology, whether familial or sporadic, we then proceed with clinical exome and mitochondrial genome sequencing of all known associated ataxia genes.

If whole-exome or whole-genome sequencing is not feasible, we obtain alpha-fetoprotein and cholesterol levels to look for evidence of oculomotor apraxia types 1 and 2, AT, and AT variants in cases where these diagnoses are consistent with the history and examination.
We also check cholestenol levels for evidence of cerebrotendinous xanthomatosis if there are any features of this disorder.

Question 28

Helpful age limit to suspect dominant or recessive hereditary ataxia

Answer 28

25 years

Question 29

Does the absence of family history rule out hereditary ataxia?

Answer 29

No

Question 30

most common SCAs

Answer 30

SCA1, SCA2, SCA3, and SCA6

In these disorders, symptoms typically begin in middle age, and most patients require a wheelchair by 10 to 15 years after symptom onset due to the degree of ataxia.

Πιο συχνή ωστόσο φαίνεται να είναι η SCA27B (10-20% LOCA)!

Question 31

Classification of spinocerebellar ataxias

Answer 31

Question 32

Spinocerebellar ataxia pathogenesis

Answer 32

Several types of SCAs (SCA1, SCA2, SCA3, SCA6, SCA7, SCA12, SCA17) and DRPLA are associated with expansion of trinucleotide CAG repeats in the region that encodes for polyglutamine tracts in the protein products.

Question 33

Spinocerebellar ataxias prognosis

Answer 33

All SCAs are characterized by a progressive course, but there is tremendous variation in rate of progress and prognosis.
Time from symptom onset to death typically ranges from
one to three decades.
However, progression is particularly slow in SCA5, SCA13, and SCA21, and patients with SCA8 and SCA11 typically have a normal lifespan

Question 34

Episodic ataxias

Answer 34

There are seven varieties of dominantly inherited episodic ataxias, called EA1 through EA7.
Of these, EA1 and EA2 account for the majority of reported cases.
The diagnosis of EA is typically made based upon the history and clinical features.
Molecular genetic testing is clinically available for some of these disorders.
Both EA1 and EA2 respond to treatment with acetazolamide (250 to 750 mg/day).

In EA1 phenytoin and carbamazepine can be tried if treatment with acetazolamide is unsuccesful whereas in EA2 phenytoin and carbamazepine may exacerbate symptoms!

++ Σε αυτές πρέπει να προστεθεί και η SCA27B γιατί συχνά ξεκινά ως επεισοδιακή αταξία!

Question 35

Episodic ataxia type 1 clinical findings

Answer 35

• Onset childhood–2nd decade
• Episodes of ataxia and dysarthria lasting seconds to minutes
• Provoked by startle and movements
• Neuromyotonia, seizure, and skeletal deformities in some
• Interictal periorbital or hand muscle myokymia but no interictal ataxia

Question 36

Episodic ataxia type 2 clinical findings

Answer 36

Onset childhood–teens

Episodes of ataxia and dysarthria lasting from a few hours to a few days, nausea, headache, dystonia and seizures in some, hemiplegia in 10%
Migraine may be present

Provoked by emotional stress, physical exertion, heat, alcohol

Interictal downbeat or gaze-evoked nystagmus

Interictal ataxia may slowly progress and become persistent,
weakness may occur before or during spells

MRI may demonstrate atrophy of cerebellar vermis

Question 37

Episodic ataxia 2: gene mutation and which other disorders are associated with same gene

Answer 37

CACNA1A

different mutations in the same gene lead to SCA6 and familial hemiplegic migraine

Question 38

Most common hereditary ataxia

Answer 38

Friedreich ataxia

Question 39

Friedreich ataxia etiology

Answer 39

autosomal recessive genetic disorder

Most cases are caused by biallelic loss-of-function expanded trinucleotide (GAA) repeat variants in intron 1 of the frataxin (FXN) gene, which encodes the mitochondrial protein, frataxin

5-33 GAA επαναλήψεις = φυσιολογικός γονότυπος
34-65 GAA επαναλήψεις = προμετάλλαξη με πιθανότητα δημιουργίας πλήρους μετάλλαξης σε επόμενες γενιές
66-1700 GAA επαναλήψεις = πλήρης μετάλλαξη/ παθολογικός γονότυπος

Question 40

Friedreich ataxia clinical findings and age of onset

Answer 40

Onset is typically between the ages of 2 and 25 years.

FRDA is characterized by
- a slowly progressive gait and limb ataxia
- absent lower limb reflexes
- reduction or loss of proprioception and vibration sense

The legs may be spastic, and extensor plantar responses may be present.
Rarely, other movement disorders, including chorea, or spastic paraparesis may occur.
Kyphoscoliosis is an early sign; pes cavus deformity (κοιλοποδία) occurs later.

Hypertrophic cardiomyopathy (affecting up to 85 percent of patients by early adulthood) is a prominent feature of classic FRDA and leads eventually to death.

Diabetes mellitus occurs in later stages in up to 25% of patients

Late-onset FRDA: between 26 and 39 years of age
very lateonset FRDA: after 40
These variants account for approximately 10–15% of known FRDA cases.
Another variant is FRDA with retained reflexes, which also has a more benign course.

Question 41

Friedreich ataxia diagnosis

Answer 41

The diagnosis of Friedreich ataxia is based upon clinical findings and should be confirmed by genetic testing for pathologic repeat expansion of the FXN gene

Question 42

Friedreich ataxia management

Answer 42

• An occupational and physical therapy program should be initiated early.
• Periodic evaluation of cardiac function is required.
• Similarly, patients should be monitored for the development of dysphagia, scoliosis, vision loss, hearing loss, bladder dysfunction, sleep apnea, and diabetes mellitus. Genetic and psychological counseling are also important.

*For patients 16 years of age and older with Friedreich ataxia, we suggest treatment with omaveloxolone.
However, given the modest benefits and potential burdens of treatment, some patients and families may reasonably choose not to start omaveloxolone until more experience with the drug accumulates.
Patients require monitoring of liver function tests, brain natriuretic peptide (BNP), and lipids during treatment.

imporved modified Friedreich Ataxia Rating Scale

Question 43

most common inherited progressive ataxia of childhood

Answer 43

Ataxia-Telangiectasia

Question 44

Ataxia-Telangiectasia etiology

Answer 44

autosomal recessive genetic disorder

pathogenic variants in the ataxia-telangiectasia mutated (ATM) gene.

In most cases, the AT phenotype results from biallelic loss-of-function variants leading to absent or defective ATM kinase.

Question 45

Ataxia-Telangiectasia clinical findings

Answer 45

Classic AT –
Classic AT usually presents either at birth, with partial combined immunodeficiency, or in early childhood, when neurologic abnormalities begin.
Young children develop progressive cerebellar ataxia, abnormal eye movements, extrapyramidal motor dysfunction, and oculocutaneous telangiectasias.

Progressive pulmonary disease and hematologic malignancy are major causes of morbidity and mortality.

Variant AT –
Variant AT presents slightly later, by the age of 10 years in most cases, with milder cerebellar dysfunction and extrapyramidal movement disorders (eg, tremor, dystonia).
Compared with classic AT, cancer tends to occur later in life and may include a higher proportion of solid tumor malignancies.

AT heterozygotes –
AT heterozygotes have none of the classical clinical manifestations of AT, but they do have a higher incidence of coronary heart disease and malignancy at a younger age compared with the general population

Question 46

Ataxia-Telangiectasia diagnosis

Answer 46

AT is typically suspected either based on abnormal results of a newborn screen for severe combined immunodeficiency (SCID) or the onset of ataxia and other neurologic abnormalities in early childhood.

The diagnosis is established by genetic testing confirming biallelic pathogenic variants in the ATM gene

Question 47

Ataxia-Telangiectasia laboratory and imaging findings

Answer 47

Elevated α-fetoprotein level is found in more than 90% of patients.
Serum levels of IgA, IgE and IgG are decreased.

MRI of the brain initially demonstrates a normal cerebellum, but shows considerable cerebellar atrophy by the age of 10 years

Question 48

Ataxia-telangiectasia management

Answer 48

monitoring for malignancies.
In those with tumors, dosages of radiation therapy need to be adjusted because of increased sensitivity to radiation.

The overall prognosis is grave.
Most patients are wheelchairbound by the age of 10, and most die before the age of 30.

However, progression is slower in patients with disease of later onset (>30 years).

Question 49

Ataxia with isolated vitamin E deficiency etiology

Answer 49

autosomal recessive disease

Mutations in the gene for α-tocopherol transfer protein,
which is responsible in the liver for incorporating tocopherols into very-low-density lipoproteins for subsequent release into the circulation.

In affected patients, therefore, vitamin E is rapidly eliminated, resulting in deficiency despite adequate enteric resorption

Question 50

Ataxia with isolated vitamin E deficiency clinical findings

Answer 50

The diagnosis of AVED should be considered if a patient
presents with clinical features suggestive of FRDA, but
molecular testing for the FRDA gene mutation is negative.
Cardiomyopathy, similar to the one in FRDA, is present in 20% of affected patients.

Heterozygotes are phenotypically normal but have serum vitamin E concentrations 25 percent lower than normal.

Question 51

Ataxia with isolated vitamin E deficiency treatment

Answer 51

Oral supplementation of vitamin E at a dose of 800–2000 IU daily or twice daily is the treatment of choice.

Question 52

Abetalipoproteinemia (Bassen-Kornzweig syndrome)
etiology and clinical findings

Answer 52

autosomal recessive disorder caused by mutations in the microsomal triglyceride transfer protein (MTTP) gene.
The neurologic manifestations result from the inability to absorb and transport vitamin E

progressive ataxia, sensory-motor neuropathy, and vision impairment with retinitis pigmentosa (μελαγχρωστική αμφιβληστροειδοπάθεια)

Question 53

Abetalipoproteinemia (Bassen-Kornzweig syndrome) diagnosis and management

Answer 53

The diagnosis is made in the setting of the typical clinical findings accompanied by laboratory findings of:

• acanthocytosis
• very low triglyceride and total cholesterol levels
• absent beta-lipoproteins
• Vitamin E levels (alpha-tocopherol and gamma-tocopherol) undetectable or very low.

Molecular genetic testing for mutations of the MTTP gene confirms the diagnosis

Neurologic manifestations can be prevented and partially reversed with the administration of vitamin E, 150 mg/kg per day along with other fat-soluble vitamins

Question 54

Hereditary motor and sensory neuropathy type IV (Refsum disease) clinical findings and management

Answer 54

Retinitis pigmentosa (μελαγχρωστική αμφιβληστροειδοπάθεια), peripheral polyneuropathy, cerebellar ataxia, elevated CSF protein, sensorineural deafness, ichthyosis, anosmia, abnormal accumulation of phytanic acid

Dietary restriction of phytanic acid intake – Foods to avoid include

*Meat or fats from cows and other ruminating animals
*Baked goods containing animal fats
*Dairy products

Question 55

Cerebrotendinus xanthomatosis (χολεστανόλωση): clinical findings

Answer 55

Systemic symptoms associated with CTX include intractable diarrhea, premature cataracts, tendon xanthomas, premature atherosclerosis, and cardiovascular disease.
The systemic features typically present earlier than the neurologic manifestations.

Neurologic dysfunction, including intellectual disability, dementia, epilepsy, parkinsonism, myelopathy, and neuropathy, is usually apparent by late childhood or early adulthood, and progresses during adulthood.

Question 56

Cerebrotendinus xanthomatosis: diagnosis

Answer 56

The diagnosis of CTX is suggested by the typical constellation of CTX symptoms, which are seen in most patients with the disorder. These symptoms are:

*Neonatal cholestatic jaundice
*Infantile diarrhea
*Noncongential cataracts presenting in childhood
*Tendon xanthomas presenting during adolescence or early adulthood
*Progressive neurologic dysfunction beginning in late childhood or early adulthood

Elevated levels of serum cholestanol and serum and urine bile alcohols are supportive of the diagnosis, which can be confirmed with genetic testing.

Laboratory testing for serum cholestanol and serum and urine bile alcohols should be performed for children with bile disorders, diarrhea, or cataracts.

Molecular genetic testing can detect pathogenic CYP27A1 variants in up to 99 percent of affected individuals

Question 57

Cerebrotendinus xanthomatosis: treatment

Answer 57

For children and adults with CTX, we recommend treatment with chenodeoxycholic acid

The suggested dose of CDCA is 250 mg three times a day for adults

It is important to begin treatment before the onset of neurologic dysfunction in order to prevent irreversible neuronal injury; clinical improvement in established disease is uncommon

Question 58

Rare treatable mitochondrial disorder cause of ataxia

Answer 58

Familial ataxia with coenzyme Q10 deficiency

Question 59

Neimann Pick type C etiology and clinical findings

Answer 59

autosomal recessive pattern

Pathogenic variants in the NPC1 gene (95 %) and NPC2 gene (4%).
Both result in impaired cellular processing and transport of low-density lipoprotein cholesterol and other macromolecules, including glycosphingolipids.

Niemann-Pick disease type C can present from the perinatal period until late adulthood.
Systemic involvement of liver, spleen, or lung is present in ≥85 percent of patients, and precedes the development of neurologic symptoms

Most patients with NPD-C have disease onset in middle to late childhood, typically with:
- cerebellar symptoms
- slow cognitive deterioration
- vertical supranuclear gaze palsy
- progressive dystonia, dysarthria, and dysphagia.

• Gelastic cataplexy (ie, cataplexy triggered by laughter) with abnormal polysomnograms is a prominent feature in up to 50 percent of children
• In adults, dementia, depression, bipolar disease, or schizophrenia may be the only symptoms!

Question 60

Neimann Pick type C diagnosis and management

Answer 60

The diagnosis of NPD-C is based upon abnormal biomarker screening for oxysterols and genetic confirmation of a pathogenic variant involving both alleles of NPC1 or NPC2.

For children and adults with NPD-C who have mild to moderate neurologic, psychiatric, or cognitive manifestations, we suggest miglustat treatment

Question 61

CANVAS: etiology and clinical findings

Answer 61

Most familial and sporadic forms are caused by homozygous AAGGG repeat expansion within intron 2 of the RFC1 gene, which encodes a large subunit of replication factor C and is involved in DNA synthesis and repair.

Clinical features of CANVAS include
* gait imbalance in all
* variable presence of dysesthesia, oscillopsia, impaired vibratory sensation, and loss of ankle reflexes.
* motor system involvement with upper and/or lower motor neuron signs (up to half of patients) or, less commonly, parkinsonism
* All patients have impairment of the oculocephalic reflex (doll’s eyes or visually enhanced vestibulo-ocular reflex), which is tested in conscious patients by turning the head quickly from side to side while the patient fixates on an immobile target; the abnormal response is that the eyes fall short of the target due to a hypoactive vestibulo-ocular reflex and make a compensatory saccade (“catch-up” saccade to reach the target).
* symptoms of autonomic dysfunction are common

Question 62

CANVAS: imaging and neuropathologic findings

Answer 62

Brain MRI frequently reveals atrophy of the anterior and dorsal cerebellar vermis.
Electrodiagnostic testing shows loss of sensory nerve action potentials with or without motor neuron involvement

Neuropathologic changes involve a dorsal root ganglionopathy with secondary spinal cord degeneration in the posterior columns, atrophy of cranial sensory ganglia, and cerebellar atrophy with loss of Purkinje cells, mainly in the vermis

Question 63

Wilson disease: etiology and clinical findings

Answer 63

autosomal recessive disorder of copper metabolism caused by mutations of the ATPase copper transporting beta (ATP7B) gene

Impaired biliary copper excretion leads to accumulation of copper in several organs, most notably the liver, brain, and cornea. Over time, the liver is progressively damaged and eventually becomes cirrhotic.
A minority of patients develop acute liver failure, most often in the setting of advanced fibrosis of the liver.

Neurologic complications:
- ataxia
- tremor
- choreoathetosis
- bradykinesia
- psychiatric symptoms of depression, paranoia, or delusions.

Question 64

Wilson disease: diagnosis

Answer 64

Initial diagnostic testing includes
- an ocular slit-lamp examination (or anterior segment optical tomography)
- 24-hour urinary copper excretion
- serum ceruloplasmin.

Liver biopsy is not always necessary because the diagnosis can be established in some patients with noninvasive testing and ocular examination

For patients in whom the diagnosis remains suspected but not established based on initial testing, additional studies include liver biopsy to assess hepatic copper concentration and/or molecular genetic testing to evaluate for pathogenic (disease-causing) variants affecting both ATP7B alleles.

https://www.uptodate.com/contents/wilson-disease-clinical-manifestations-diagnosis-and-natural-history?search=ataxia&topicRef=14134&source=see_link#H69501155

Question 65

Wilson disease: management

Answer 65

Question 66

Whipple disease: etiology and clinical findings

Answer 66

bacillus Tropheryma whipplei

arthralgias, weight loss, abdominal pain, and diarrhea.

Central nervous system involvement is often asymptomatic; those with symptoms most often present with cognitive change, altered consciousness, and/or a supranuclear gaze palsy, but cerebellar ataxia can occur.

Less common but specific findings include oculomasticatory myorhythmia (continuous pendular convergence oscillations of the eyes combined with concurrent contractions of the masticatory muscles) and oculo-facial-skeletal myorhythmia.

Question 67

Whipple disease: diagnosis and management

Answer 67

The diagnostic evaluation includes CSF PCR for T. whipplei and confirmatory small bowel biopsy

penicillin or ceftriaxone, followed by maintenance therapy with oral trimethoprim-sulfamethoxazole

TMP-SMX maintenance therapy is given for 12 months.