2 type disproportionate anterocollis in Parkinson syndromes

Neurology 2020 AAN PO1.274  Clinical subtypes of disproportionate anterocollis in parkinsonian syndromes Revuelta G, Factor S. 


Myopathic subtype-- neck extensor weakness and limited range of motion, neck extensor myopathy on EMG,


dystonic subtype-- no weakness, full range of motion, laterocollis/torticollis and hypertrophy. 

Other Mitochondria disease: MNGIE

MNGIE-  aut rec, presents with abdominal pain, malabsorption and weight loss.  Peripheral neuropathy and leukodystrophy occur.Serum lactate is almost invariably high.  Elevated thymidine is seen, and WBC shows decreased thymidine phosphorylase (buffy coat??).

Clinical presentations of mitochondrial cytopathies MELAS , MERRF and LHON

Melas- hypoacusis, ataxia, dementia, opthalmoplegia, encephalopathy, stroke like syndromes, exercise intolerance, proximal myopathy, type 2 diabetes.  Due to point mutation, can occur at most ages and mimic multiplle sclerosis with progressive or remitting and relapsing presentations

MERRF  isolated myoclonic epilepsy with or without ataxia, myopathy, peripheral neuropathy, and multiple lipomas in head region.  Neuropsychiatric manifestations including OCD, depression, psychosis and type two diabetes are common.  Any age of presentation to mid 40s.  Progressive decline

LHON-  painless, rapidly progressive vision loss with centrocecal scotoma in teenagers or young adults with male predominance (65-35).  Can mimic MS.

Mitchondrial cytopathies

visit http://www.mitomap.org/ for detailed information on cytopathies

Leigh disease (Complex 1>complex 2,3) aut rec
Succinate dehydrogenase gene (SDHB c and D) paraganglioma and pheochromocytoma, aut dom
polymerase gamma (POLG) mutations-- Alpers syndrome (hepatoencephalomyopathy), CPEO, spinocerebellar ataxia, sensory ataxia neuropathy with dysarthria and opthalmoplegia (SANDO),
ECGF1 (thymidine phosphorylase)- MNGIE

GI differential
liver involvement- Alpers syndrome
irritable bowel, intestinal pseudoobstruction--MELAS
severe GI dysfunction--MNGIE

Neuropathy-- MNGIE, SANDO

Historical points to ask about: deafness, short stature, early cardiac death in family, muscle discomfort or exercise intolerance, early onset DM.
Barth syndrome-- deafness and dystonia

Diagnostic tests
elevated lactate-- 60 percent sensitive, not completely specific
lactate/pyruvate ratio in CSF- may differentiate pyruvate dehydrogenase deficiency from primary mit. cytopathy
plasma amino acids-  elevated alanine may be seen
elevated CPK- may be seen in myopathy, not specific
alpha feto protein- may be seen in Alpers' syndrome early along with increased GGTPand others
thymidine levels-- high in MNGIE
urine organic acids-- high levels of ethylmalonic acid prompts ETHE1 gene for encephalopathy
     high 3 methyl glutaconic acid prompts look for tafazzin mutation for Barth syndrome
folate, B12, vitamin E- may be low in percentage coincidentally or secondarily

MRI- high T2 signal in putamen leading to striatal necrosis characterizes Leigh disease
occipital stroke-- consider MELAS

Cerebral palsy for adult neurologists: pearls

1.  Gross Motor Functional Classification System is most widely used

Level I  Ambulatory in all settings
Level II Walks without aids but has limitations in community settings
Level III Walks with aids
Level IV  Requires wheelchair or adult assistance
Level V  Fully dependent for mobility

Of all CP patients, 40 % are level I, and 66 % are levels 1-3 (ie. ambulatory)

2.  O CP patients, approximately one third will have spastic quadriplegia, one third spastic hemiplegia, one fifth spastic diplegia, and the rest either dyskinetic or ataxic-hypotonic CP.  It is rare for CP patients with spastic hemiplegia or spastic diplegia to be nonambulatory, but 75% of spastic quadriplegia patients are not ambulatory.  Those same patients are much more likely to suffer comorbidities such as epilepsy. 

3.  Genetic defects such as DCX and LISI can be sought, and coagulation pathway abnormalities (Leiden mutation eg.) among those suffering from placental thrombosis.

Care of hydrocephalus in adults pearls

1. Hydrocephalus may be decreasing.  Reasons may include higher threshold for surgery (artefact of practice) increased folate in pregnancy causing less myelomeningocoele.

2.  Unchanged CT scan does not exclude obstruction

3.  ETV or endoscopic third ventriculostomy is a more recent alternative to shunting in a highly select group of patients.  The procedure is more prone to immediate catastrophe, but less to long term infection, although obstruction can occur years later (as it can with any shunting procedure).  ETV may be best for older children with obstructive hydrocephalus or aqueductal stenosis.

4.  A top down approach to assessing meningocoele would sequentially assess hydrocephalus, Chiari malformation, syringobulbia.syringomyelia, tethered cord.

Diagnostic criteria for FXTAS (fragile x associated tremor ataxia syndrome)

Molecular-- CGG repeat 55-200
Clinical
   Major intention tremor, cerebellar ataxia
   Minor  Parkinsonism, moderate to severe short term memory loss, executive function deficit
Radiologic
   Major white matter lesions in middle cerebellar peduncles (MCP sign)
   Minor  lesions in cerebral white matter, moderate to severe brain atrophy

Diagnostic categories

Definite-- one major clinical, and one major radiologic, or present inclusions at autopsy
Probable-- two major clinical, or one minor clinical and one major radiologic
Possible-- one major clinical and one minor radiologic

Dystrophinopathies in adults: pearls

See also http://emgnotes.blogspot.com/2010/01/dystrophinopathy-clinical-diagnostic.html and here are ten more pearls

1.  Many DMD patients now live into 30s and 40s as do carriers or those with BMD.  DMD frequency is about 1:3500 whereas BMD is 1:15,000 to 1:35,000.

2.  Dystrophinopathy should be suspected in a child or adult with the following clinical signs/symptoms:  progressive skeletal muscle weakness, increased CPK, intellectual impairment, myalgias, or cardiomyopathy.

3. BMD patients by convention ambulate after 16.  In 40 + year olds, isolated quad weakness can be confused with IBM.  EKG findings are similar to DMD  (arrythmias or decreased EF requiring Ace inhibitors).  Chronic respiratory insufficiency can be associated with right heart failure.

4.  Minimally symptomatic BMD with exertional intolerance, myalgia, myoglobinuria, or elevated CK diagnostic yield increases with subtle signs such as clumsy as child, toe walking, positive family history, calf or tongue hypertrophy, or myopathic units on EMG. 

5.  All patients regardless of symptoms should have periodic pulmonary function testing, EKG, and echocardiography.

6.  Vaccinations including pneumococcal and influenza are recommended with low threshold for treating potential infections with antibiotics.

7.  Anesthetic risks mandate patients wear a med alert bracelet. These risks are minimized with nondepolarizing muscle relaxants. 

8.  Bowel program plus suction continuous via gj tube reduces abdominal pain.  Restricted jaw opening can mandate placement of a tube. 

9. Consider seated position or other creative safety measures during surgery if possible and if indicated.

10.  PT with range of motion and stretching exercises are hallmark.

Autosomal dominant ataxias with known causation

Most common types are SCA I,II, III, VI which comprise > 50 % cases in USA.  * indicates caused by polyglutamine CAG repeat expansion

SCA I--*-- begins as gait disorder, progresses to four extremity ataxia with dysarthria leaving patient wheelchair bound within 15-20 years.There is phenotypic variability and anticipation (genetically).  Clinically there is involvement of cerebellum with neuronal dropout of Purkinje cell layer and clinical involvement of the brainstem.  No supratentotial involvement.  Not as common as type II but well worked out molecularly,

SCA II--*--characterized by ataxia, dysarthria, slow saccades and neuropathy.  Originally Cuban description.  Very common worldwide, especially in India.  Slow saccades are not pathognomonic, they also are seen in SCA I and III.   Dementia, areflexia, myokymia also are seen. Gene expansion includes cytoplasmic protein ataxin, function of which is unknown.  Anticipation is marked, and disease may present in one generation in old age, in the next much earlier.  Number of repeats are 35-77 , with 32-34 "zone of reduced penetrance."

SCA III--*--Very common, is aka Machado-Joseph disease.  Presents with ataxia, eye movement abnormalities (bulging eyes, opthalmoparesis, staring eyes), speech and swallowing abnormalities.  Pathologic abnormalities include cerebellar afferent and efferents, pontine and dentate nuclei, substantia nigra, subthalamic, GP, cranial motor nuclei and anterior horn cells.  Ataxin 3 gene is at fault.  Repeats: normal 12-42, high is 52-84.  Early onset rigidity and dystonia (largest expansions), middle onset adult ataxia, late onset neuropathy (smallest expansions).  A few patients have Parkinson's that is dopamine responsive and even fewer have RLS.  Peripheral involvement is especially variable.  MRI shows range from fourth ventricle enlargement to severe olive sparing spino pontine cerebellar atrophy.

SCA-- V-- "Lincoln family ataxia"--slowly progressive dominant ataxia found in grandparents of Lincoln.  SPTBN2 gene ecoding B III spectrin is at fault. 

SCA VI  --*--  milder disease, pure cerebellar associated with normal lifespan.  Presentation is gaze evoked nystagmus, dysarthria, onset at age 50 or so, impaired vibratory and position sense.Its fairly common in Japan and in Germany.  Caused by expansion/repeat in voltage dependent calcium channel,same gene  that causes episodic ataxia type 2 and familial hemiplegic migraine.  However, mutations in these conditions in the same gene are different mutations.

SCA 7--*-- cerebellar brainstem disease associated with retinal degeneration and blindness.  It has striking instability of transmission especially with paternal transmission, with cases in utero and in childhood.

SCA 8--*-- classical presentation of disease with gait and limb ataxia, swallowing speech and eye movement abnormalities.  Most have progressive ataxia.

SCA 10 --*-- Mexicans with cerebellar symptoms and seizures.  Extremely large expansion is found in SCA 10 gene. Ashizawa.

SCA 11--*--  2 British families reported with benign gait and limb ataxia.  TTBK2 gene.

SCA 12 --*--PP2R2 gene with dominant ataxia presenting with upper extremity tremor, progressing to head tremor, bradykinesia, abnormal eye movements.  Onset 8-55 years.

SCA 13 --*-- dominant ataxia, may present in childhood with MR, dysarthria, nystagmus, +/- hyperreflexia.  Due to KCNC3 gene mutation in voltage gated K channel subunit.

SCA 14 --not repeat--slowly progressive ataxia with dysarthria in early adulthood.  May be pure cerebellar or accompanied by myokymia, hyperreflexia, axial myoclonus, dystonia and vibratory sense loss. 

SCA 15-16-- allelic (ie same allele) disorder occurring in Austrailian and Japanese families, slowly progressive pure cerebellar disorder.  Dysarthria, horizontal gaze evoked nystagmus, sometimes head tremor.  Disease is due to deletions in IPTR gene

SCA 17 --*--Widespread cerebral/cerebellar dysfunction, rare in US, more common in Japan.  Presents with gait and limb ataxia, psychiatric dysfunction, EPS, seizures, may resemble Huntington;s disease.  MRI shows widespread cerebral and cerebellar dysfunction.  Onset in mid to young adulthood.

SCA 26 -- Norwegian pure cerebellar ataxia that maps closely to gene affecting Cayman ataxia and SCA 6 with Purkinje cell degeneration. 

SCA 27-- Dutch disease manifests with hand tremor in childhood.

DRPLA-- *--  progressive ataxia, choreoathetosis, dementia, seizures, myoclonus, and dystonia. Before age 20 there are almost always seizures and a progressive myoclonic seizure like presentation.  Older patients get ataxia with choreoathetosis and dementia.  More common in Japan, but Haw River phenotype is an African American family in the Carolinas with seizures and cerebral calcifications.

episodic ataxias--EA1 and EA2 are due to mutations in K and Ca channel genes.  EA1-- patients ahve minutes of ataxia due to stress, exercise or change in posture. Patients also may have myokymia.   KCNA1 gene. EA2 has ataxia that lasts days , precipitated by stress, exercise or fatigue and is due to mutation of same gene as SCA 6 (CACNA1A4 gene). Acetozolamide may help.  Other EA's with prominent vertigo also are described.

Friedrich's ataxia, FARR, LOFA, VLOFA

Friedrich's ataxia (AR) is subclassified into classical (75%), FARR (FA with retained reflexes, adult onset), LOFA (late onset FA) and VLOFA (very late onset FA). 
In FA, pathology involves spinocerebellar tracts, lateral corticospinal tracts, posterior columns but NOT cerebellum.  Clinical features include a.  progressive gait ataxia and scoliosis  b.  gait worse in darkness (posterior column involvement)  and worsening during puberty    c.  dysarthria and hand incoordination   d.  areflexia  e. extensor plantars.  Associated features may include  e.  optic nerve atrophy (25%),  f.  SN hearing loss (10%)  g.  optic flutter or square wave jerks but not opthalmoplegia  h.  hypertrophic cardiomyoapthy (90%)  i. pes cavus  j. diabetes mellitus in 15 % 15 years after onset  j.  wheelchair bound after 15 years  k.  Death 30-70.
In FARR, LOFA, VLOFA, sporadic ataxia occurs without cardiomyopathy. Spasticity occurs, areflexia does not.  Again normal cerebellum.  Sporadic ataxia patients may warrant gene testing for frataxin.  Affected patients usually have 2 affected alleles, carriers have one.  Rarely, sequencing of second allele for FXN is needed to find a point mutation (compound heterozygosity).

Neurosarcoidosis pearls diagnosis

1.  Percent with cranial neuropathy-- 50-75 (most common VII, second II, all can be affected)

 

2.  Percent with parenchymal brain lesions-50

 

3.  Other manifestations - cognitive 20, meningeal 10-20, PN 15, seizures 5-10, spinal 5-10, myopathy 1.4-2.3

 

4.  Neuroendocrine presentations may include polydipsia, polyuria, panhypopituitarism, or massive obesity if sarcoid invades satiety center of hypothalamus

 

5.  Neuropathy can be virtually any type

 

6.  Myopathy can be acute, chronic or nodular and is usually subclinical. In contrast to steroid myopathy (the rule-out diagnosis often), sarcoid myopathy may have palpable nodules, contractures, cramps, elevated CPK, and fibrillation potentials and positive sharp waves on EMG.  Both steroid and sarcoid myopathy will have myopathic potentials.

 

7.  Contrast enhanced MRI to look for meningeal involvement is extremely important, but is not specific.

 

8.  Whole body PET imaging is better than Gallium and can be used to look for lymph nodes suitable for biopsy for diagnosis, but is not specific

 

9. CSF is normal in one third,but can show high protein, lymphocytosis, low glucose. OCB's , high IgG index

 

10.  CSF ACE levels are insensitive (24-55 %) but fairly specific (93%) for CNS sarcoid

 

11.  Heerfordt's syndrome consists of facial palsy, parotid enlargement, uveitis and fever and is considered so typical that tissue biopsy is not required

 

Persistent genital arousal syndrome: neurology of and comparison to epileptic orgasms

This post details  a  neurologic basis  to persistent genital arousal syndrome (PGAS).  The condition is characterised by unwanted repeated multiple daily episodes of sexual arousal, that often leads to dozens or hundreds of orgasms daily, relieved with masturbation briefly before recurring.  It can be lifelong, occur during pregnancy, or in the postmenopausal state.  Precipitating factors include pudendal nerve injury,  and antidepressant drugs including trazodone.  A strong association with restless legs syndrome and overactive bladder has been noted. Treatments that were successful in many patients include clonazepam, tramadol, pelvic floor massage focusing on the pudendal nerve, varenicycline,and pudendal nerve blocks.

This condition can be differentiated from orgasmic seizures, which itself needs to be divided into different entities.  Orgasms as an aura of a seizure can occur usually due to right hippocampal, but occassionally left hippocampal or left parietal epilepsy.  Reflex epilepsy after orgasm also occurs again usually after right temporal but occassionally left frontal seizures and in one case report reflected the manifestations of complete heart block, cured with a pacemaker.  Reflex epilepsy occurring as orgasmic aura has been reported after toothbrushing in one Taiwanese patient.

see pub med for references

Antiepileptic drugs and peripheral neuropathy

Effects of the antiepileptic drugs on peripheral nerve function; Boylu E, Domaç FM, Misirli H, Senol MG, Saraçoglu M; Acta Neurologica Scandinavica 121 (1), 7-10 (Jan 2010)

 

Upshot-- carbamazepine, but not valproate, oxcarbazepine and topirimate, affect nerve conduction studies among chronic takers.

Clinical pearls in diagnosis of vestibular disorders

1.  Look for nystagmus with and without fixation.  To achieve latter, either examine in a darkened room with Frenzel glasses or use opthalmoscope in one eye and cover the other.

2.  Nystagmus can be assessed with holding eyes 30 degrees from midline in 4 positions (L-R-U-D) each for 20 seconds.  Further out, and nystagmus is expected.  Use a chart to score.

3.  Nystagmus through eyelids can be confused with lid twitch.

4.  Features of central nystagmus that differ from peripheral include pure vertical, horizontal or rotatory rather than combined;  no effect of fixation;  may change direction;  central abnormality may affect pursuit or OKN. In central nystagmus, there may be a null zone near center after which nystagmus changes direction when eyes look in opposite direction.

5.  Head thust sign is a simple test at bedside, of horizontal component.  Move head rapidly a short distance horizontally in one direction and then other.  Eyes should at start be ten degrees from primary position so that after the thrust they will be near primary position.  Patient fixates on examiner's nose.  If there is a catch up saccade in one direction but not the other, that is evidence of a peripheral lesion on that side. The absence of a head thrust sign suggests a central etiology.

6.  Patients with peripheral lesions veer towards the side of the lesion when up.  Patients with central lesions often cannot stand.  Patients with central lesions are more likely to have dysarthria,  numbness or weakness.

7.  Viral labyrinthitis needs to be diagnosed after ruling out other entities.  Bacterial usually has associated mastoiditis that is identified on CT scans of the temporal bone.  Usually auditory and vestibular function both are affected with bacterial infection.

8.  Recurrent episodes that become bilateral and lead to deafness within months are associated with syphilis.

9.  Perilymh fistula often presents abruptly after a precipitating event, such as head trauma, barotrauma, strain while lifting, or sneezing.  It is very common among patients who have undergone stapedectomy for otosclerosis.  Patients with fluctuating symptoms or positive fistula test need to undergo surgery.

10. Very important: the Dix Hallpike test can be positive in central vertigo cases, including tumors, but features are different.  Central variety fails to attenuate with repeated tests, may last longer than 30 seconds, and may have fast phase downward to cheek (as opposed to peripheral which is to bottom ear and forehead). 

Classical Babinski-like signs

Extensor toe signs
Babinski response- extension of big toe, fanning of small toes with stroking plantar surface
Chaddock response- same response except stimulation is of lateral foot from lateral malleolus
Gordon leg sign-- same with stimulation of squeezing leg muscle
Oppenheim's sign-- same result with downward stroking of tibia and tibialis anterior muscle
Gonda's reflex--upward movement of big toe by moving another toe down and releasing with snap
Shaefer's sign-- Babinski response by squeezing Achilles' reflex


Non extensor toe  long tract signs
Rossolimo's sign-- same response with striking or tapping the ball of the foot
Mendel-Bechterew sign- flexion of 4 outer toes by striking dorsum of foot
Hoffman's sign-- Clawing of the thumb and all fingers by flicking distal phalanx of index finger
Gordon's finger sign-- flexion of fingers or thumb/index finger with pressure over pisiform bone
Chaddock's wrist sign- wrist flexion, extension & fanning of fingers with stimulation of ulnar side of hand
Hirschberg's sign- adduction and internal rotation while stroking the inner border of foot
Ankle clonus-- may be normal if unsustained
Patellar clonus (trepidation sign)-- lifting relaxed knee suddenly looking for increased tone

Other pathologic signs
Beevor's sign-- with lesion at T10, the patient tenses abdominal muscles and ombilicus moves upwa rds, doe to paralyzed
Mass reflex of Riddoch-sudden emptying of bowel and bladder, flexion of lower limbs and sweating.  Its released pathologically by severing spinal cord and striking skin below

Classical abnormal gaits

Tabetic (ataxic) gait
Hemiplegic gait
Steppage gait
Scissors gait
Drunken or ataxic gait
Waddling or clumsy gait
Festinating gait
Hysterical gait
astasia - abasia

metoprolol : no effect on QOL in recurrent syncope

Effect of metoprolol on quality of life in the prevention of syncope trial; Sheldon RS, Amuah JE, Connolly SJ, Rose S, Morillo CA, Talajic M, Kus T, Fouad-Tarazi F, Klingenheben T, Krahn AD, Koshman ML, Ritchie D; Journal of Cardiovascular Electrophysiology 20 (10), 1083-8 (Oct 2009)

INTRODUCTION: Vasovagal syncope is common, often recurrent, and reduces quality of life. No therapies have proven useful to improve quality of life in adequately designed randomized clinical trials. Beta-blockers have mixed evidence for effectiveness in preventing syncope. METHODS: The Prevention of Syncope Trial was a randomized, placebo-controlled, double-blind, multinational, clinical trial that tested the hypothesis that metoprolol improves quality of life in adult patients with vasovagal syncope in a 1-year observation period. Randomization was stratified in strata of patients<42 and>or =42 years old. The quality of life questionnaires Short Form-36 (SF-36) and Euroqol EQ-5D were completed at baseline and after 6 and 12 months of treatment by 204, 132, and 121 patients, respectively. RESULTS: There were 208 patients, mean age 42 +/- 18, of whom 134 (64%) were females. All had positive tilt tests. There was no improvement in quality of life during the trial in the entire group or in either treatment arm. Patients in the metoprolol treatment arm did not have improved quality of life compared to the patients in the placebo arm using either the SF-36 or EQ5D after either 6 or 12 months. Finally, there was no improvement in quality of life associated with metoprolol use in patients either<42 or>or =42 years of age. CONCLUSION: Metoprolol does not improve quality of life in patients with recurrent vasovagal syncope and a positive tilt test.

ED treatment of migraines: i-v prochlorperazine plus Benadryl beats sumatriptan

A Prospective, Randomized Trial of Intravenous Prochlorperazine Versus Subcutaneous Sumatriptan in Acute Migraine Therapy in the Emergency Department; Gutierrez FJ, Rieg TS, Moore TS, Gendron RT, Kostic MA; Annals of Emergency Medicine (Dec 2009)

STUDY OBJECTIVE: Intravenous (IV) prochlorperazine with diphenhydramine is superior to subcutaneous sumatriptan in the treatment of migraine patients presenting to the emergency department (ED). METHODS: In this randomized, double-blind, placebo-controlled trial, after providing written informed consent, patients presenting to the ED with a chief complaint of migraine received a 500-mL bolus of IV saline solution and either 10 mg prochlorperazine with 12.5 mg diphenhydramine IV plus saline solution placebo subcutaneously or saline solution placebo IV plus 6 mg sumatriptan subcutaneously. Pain intensity was assessed with 100-mm visual analog scales (visual analog scale at baseline and every 20 minutes for 80 minutes). The primary outcome was change in pain intensity from baseline to 80 minutes or time of ED discharge if subjects remained in the ED for fewer than 80 minutes after treatment. Sedation and nausea were assessed every 20 minutes with visual analog scale scales, and subjects were contacted within 72 hours to assess headache recurrence. RESULTS: Sixty-eight subjects entered the trial, with complete data for 66 subjects. Baseline pain scores were similar for the prochlorperazine/diphenhydramine and sumatriptan groups (76 versus 71 mm). Mean reductions in pain intensity at 80 minutes or time of ED discharge were 73 mm for the prochlorperazine/diphenhydramine group and 50 mm for those receiving sumatriptan (mean difference 23 mm; 95% confidence interval 11 to 36 mm). Sedation, nausea, and headache recurrence rates were similar. CONCLUSION: IV prochlorperazine with diphenhydramine is superior to subcutaneous sumatriptan in the treatment of migraine.

seroquel for refractory migrained pilot study

An Open Pilot Study Assessing the Benefits of Quetiapine for the Prevention of Migraine Refractory to the Combination of Atenolol, Nortriptyline, and Flunarizine; Krymchantowski AV, Jevoux C, Moreira PF; Pain Medicine (Dec 2009)

Background. Migraine is a prevalent neurological disorder. Although prevention is the core of treatment for most, some patients are refractory to standard therapies. Accordingly, the aim of this study was to evaluate the use of Quetiapine (QTP) in the preventive treatment of refractory migraine, defined as previous unresponsiveness to the combination of atenolol, nortriptyline, and flunarizine. Methods. Thirty-four consecutive patients (30 women and 4 men) with migraine (ICHD-II), fewer than 15 days of headache per month, and not overusing symptomatic medications were studied. All participants had failed to the combination of atenolol (60 mg/day), nortriptyline (25 mg/day), and flunarizine (3 mg/day). Failure was defined as<50% reduction in attack frequency after 10 weeks of treatment. After other medications were discontinued, QTP was initiated at a single daily dose of 25 mg, and then titrated to 75 mg. After 10 weeks, headache frequency, consumption of rescue medications, and adverse events were analyzed. Results. Twenty-nine patients completed the study. Three patients withdrew and two were lost to follow-up. Among those who completed, 22 (75.9%; 64.7% of the intention-to-treat population) had greater than 50% headache reduction. The mean frequency of migraine days decreased from 10.2 to 6.2 per month. Use of rescue medications decreased from 2.3 to 1.2 days/week. Adverse events were reported by nine (31%) patients. Conclusions. Although limited by the open design, this study provides pilot data to support the use of QTP in the preventive treatment of refractory migraine. Controlled studies are necessary to confirm these observations.

Kearn's Sayre syndrome

Rowland's diagnostic criteria

 

Obligate triad

1) Onset before 20

2) Progressive external opthalmoplegia

3) Pigmentary retinopathy

 

plus at least one of:  CSF protein>100, ataxia, cardiac conduction block

 

 

websites for genetic information

http://www.geneclinics.org/

http://www.neuromuscular.wustl.edu/

http://www.pdgene.org/

Neurotoxicology: sources of lead in adults

Lead poisoning occurs due to inhaling inorganic lead salts and fumes in processes involving remelting of lead. These include painting, printing, pottery glazing, lead smelting, welding and storage battery manufacturing. Other cases have occurred in miners, foundry and garage workers especially those who soldered radiators. Aruvedic herbal remedy for arthritis is described. Moonshine whiskey was very common in one series. The presentation is colic, anemia and peripheral neuropathy. It responds somewhat to calcium salts but not morphine (colic). Organic lead poisoning occurs in those who clean gasoline storage containers with insomnia, hallucinations, delusions and irritability. Hematologic changes are not found, and its usually reversible.

Stiff man syndrome (stiff person syndrome) Pearls

1. Insidious onset, then robotic appearance to walking and exaggerated lumbar lordosis in middle aged. Attempted passive movement causes a unique rock like immobility.

2. Trismus does not occur, and eye movements are not affected. Noise may precipitate an attack. Reflexes are normal, and lumbar spine is stiff on exam.

3. "Stiff limb" in one leg, spreading to other, has same antibodies (anti GAD) is similar to lcoalized tetanus.

4. EMG is normal and spasms disappear during sleep and anesthesia, differentiating from myokymia and Isaac's syndrome.

5. Rare paraneoplastic form usually accompanies breast cancer with antibodies to amphiphysin or gephyrin (proteins related to synaptic GABA receptors) and may be accompanied by opsoclonus or encephalopathy.

6. Differential diagnosis includes tetanus, Isaac's syndrome and myoclonic spinal neuronitis.

7. An infantile form starts at age 2 months and disappears by age 2.

Lysosomal storage diseases in adults

1. Of 45 or so diseases, all are autosomal recessive except the 3 that are X linked, namely Hunter's disease (mucopolysaccharadosis type II), Fabry's, and X linked myopathy with cardiomyopathy (lysosomal associated membrane protein 2, or LAMP 2).

2. GM2 can resemble Friedrich's ataxia, but unlike Friedrich's has hyperreflexia, episodic psychosis, and absent cardiomyopathy and scoliosis which should give away the diagnosis.

3. Dementia is common, and is a presenting feature of Kuf's disease type M and adult onset MLD. Dementia is most common presenting feature of adult onset mannosidosis, fucosidosis, aspartylglucosaminuria, Niemann Pick type c (along with vertical gaze palsy, dystonia, and dysarthria)

4. Progressive myoclonic epilepsy occurs in Kufs disease type A with spike wave on EEG and photosensitivity at low flash frequencies (see Berkovic 1988 Brain for review article).  Type B is characterized by dementia, ataxia,  EPS and facial dyskinesias.  Sialodosis type I aka cherry red spot myoclonus has treatment resistant epilepsy with macular cherry red spot and abnormal neuraminidase in skin fibroblasts.

5.  Late onset myopathy occurs in Pompe's disease, with high CPK, accumulated glycogen in vesicles, and deficient alpha glucosidase which is hard to measure.  Danon disease is X linked recessive and has hypertrophic cardiomyopathy and muscle weakness, and muscle biopsy shows autophagic vacuoles with glycogen. Its due to LAMP 2 deficiency.  There is mild MR and usually, death before 30. 

Managing adults with hydrocephalus : pearls

This post assumes patients who received a shunt as a child has problems as an adult

1. Signs of shunt malfunction/ increased ICP. On PE look for VI n palsy, papilledema, +/- reliability of shunt pump test

2. On history consider HA worse in AM or with recumbency, associated vomiting with relief, and diplopia suggest raised intracranial pressure. If HA is worse when up, consider low pressure headache

3. On imaging, assess all 4 ventricles independently, look for periventricular edema, edema around proximal shunt tip, loss of cerebral sulcal pattern near vertex, or loss of CSF spaces in basal cistern and Sylvian fissure. ALWAYS compare to prior scan closely.

4. ETV or endoscopic third ventriculostomy is used in some patients especially with third ventricular obstructions. ETV has a risk of catastrophe, a higher risk of immediate failure, a lower risk of long term failure but still can obstruct years later (unlike most standard shunts). ETV has the compelling advantage of a lower infection risk.

5. Patients with myelomeningocoele should be evaluated in a top down manner: shunt obstruction, Chiari malformation, syringomyelia/syringobulbia, and tethered cord. Often neurosurgeons will want to surgically manage the shunt to make sure it is working before embarking on other issues in these cases. An example case in Continuum was a patient who had presented with hand weakness and syringomyelia, but who had massively dilated ventricles and whose primary problem was in fact the shunt dysfunction.

Fragile X tremor ataxia syndrome (FXTAS)

FXTAS is due to premutation, and an excess amount of FRMP protein (50-200 repeats). Not all carriers develop FXTAS. Features include

1. usually presents with intention or action tremor with handwriting or using utensils

2. above is followed by ataxia with falls and unstable gait
above occurs in male carriers at a rate of 17% by 50's, 38 % by 60's, 47 % by 70's and 75 % by 80's. Women have less FXTAS with 8 % of those with premutation affected.

Other neurologic features
1. painful neuropathy

2. autonomic dusfunction (erectile dysfunction, hypertension, OH, urinary urgency and frequency, and incontinence.  Girls develop premature ovarian insufficiency or POI. 

3. White matter abnormalities (increased T2 intensity)especially bilateral cerebellar peduncles but elsewhere in deep white matter(seen in 60 % males, 13 % of females)

4. Executive dysfunction, short term memory loss, disinhibition and dementia

5. Unique eosinophilic intranuclear inclusions in neurons and astrocytes especially in the hippocampus and in the limbic system that are tau negative. They also occur in the PNS including the pericardiac and mesenteric ganglia and Leydig cells of testes.

6. Testosterone deficiency

7. Anxiety, social phobia and depression

8. Women with FXTAS : 43 % have fibromyalgia and 50 % have thyroid disease usually hypothyroidism

9. 2-3 per 100 develop multiple sclerosis and some develop Alzheimers

Treatment: SSRI's for anxiety, lithium for depression

Fragile X syndrome (FXS) clinical features

1. long face
2. prominent long ear pinnae
3. high arched palate
4. mitral valve prolapse
5. dilated aortic arch
6. flat feet
7. hyperextensible finger joints in childhood
8. macroorchidism (testicular volume greater than 30 cc in adulthood)
9. soft or velvet like skin.
10. Daughters can receive premutation only, sons cannot receive gene from their father
11. Single palmar crease

rare problems-- elasticity leads to increased hernias, and dilation of ureteric root leads to hydronephrosis.

Neuropsych
1. hyperarousal to stimuli with increased sympathetic response
2. Agression, anxiety
3. Concrete thinking
4. Dramatic decline of cognition in middle or later life, due to FRMP regulating amyloid precursor protein (APP) leading to coexisting Alzheimer's disease
5. Men typically are not sexually active and do not marry (not invariable)

Morvan syndrome aka "Choree Fibrillaire"

Four cardinal features of Morvan syndrome are

1. Neuromyotonia or myokymia

2. Dysautonomia (esp hyperhidrosis, hypersalivation, labile hypertension). Weight loss is common.

3. Severe insomnia

4. Fluctuating encephalopathy with vivid hallucinations

Other notes-- MRI and random eeg is often normal. Patients are usually young males, EMG and PSG are not normal, and VGKC's are often present. Differential includes FFI, CJD, rabies virus, and Lewy body disease. The key clinical finding that differentiates is the dysautonomia and neuromyotonia. Often is fatal, but Ligouri et al. reversed one case with plasma exchange.

Ligouri R, Vincent A, Clover L, et al. Morvan's syndrome. Peripheral and central nervous system and cardiac involvement with antibodies to voltage gated potassium channels. Brain 124: 2417, 2001.

Note-- there is a second "Morvan's disease" that refers to atrophic changes in bone, skin, muscles of hand in syringomyelia.

Clinical spectrum of disease of VGKC

Voltage gated calcium channels are seen in a variety of neurologic diseases. They include

1. Autoimmune neuromyotonia (formerly Isaac's syndrome)
2. Morvan's syndrome (encephalopathy and myotonia). Augustus Morvan (1870) "la choree fibrillaire." see separate post on Morvan's in this blog
3. Encephalopathy without neuromuscular excitability--clinical syndrome consists of a) clinically indistinguishable from paraneoplastic limbic encephalitis (PLE) b) subacute cognitive impairment with behavioral changes and temporal lobe seizures c) FLAIR and T2 changes in mesial temporal lobes on MRI d) temporal lobe eeg abnormalities e) association with hyponatremia f) male predominance g) dramatic response to IVIG or steroids
4. Are occassional cases with associated cancer, especially lung and thymus carcinoma, but these are typically associated with "other" paraneoplastic markers and symptoms and are minority
5. A similar presentation and responsiveness to treatment occurs in VGKC negative patients who have anti hippocampal neuropil antibodies.

Coccidiodal meningitis and brain abscesses: analysis of 71 cases at a referral

Drake KW, Adam RD.  Neurology 2009; 73:1780-1786

 

Most patients present with headache only (77%) while 23 % had nuchal rigidity, 39 % had mental status changes,  and one third focal signs especially gait disturbance or ataxia, may be due to hydrocephalus.   Risk factors are HIV/chronic steroids but not diabetes.  Also, liver failure, hem/lymph malignancies, and ESRD.  Increased risk for males (2:1), Hispanic, black and Asian patients in endemic areas (black patients have 6:1 risk).  CSF had mononuclear pleocytosis, 69 % had abnormally low glucose, occasionally high protein or eosinophils.  CSF antibody/culture often negative on presentation (50 %), but in those patients, serum antibody test is usually positive. Also CSF cultures or brain biopsy occasionally used for diagnosis.   Imaging may show basilar meningitis or hydrocephalus and vasculitic infarcts.  Many patients had antecedent illnesses, including respiratory, that may or may not have been diagnosed as coccidio  or occasionally  osteomyelitis, lymphadenitis, skin lesions, and soft tissue masses.  Treatment is with azoles, esp. fluconazole which has supplanted amphotericin and others.  Relapse can occur years or even decades later if azole therapy is stopped.  Shunts are frequently needed for treatment of hydrocephalus.  Prognosis is now good for those compliant with therapy.

Idiopathic intracranial hypertension in men

NEUROLOGY 2009;72:304-309

66 men out of 721 consecutive patients were studied.  The takeaways are that men

1.  Men were less likely to have HA (55 v. 75 %) but more likely to have visual disturbance.  Acuity and fields were worse and men had about twice the risk of having permanent visual sequelae.

2.  Men were more likely to have sleep apnea (24 v. 4%)

3.  Tinnitus was less common in men (20 v. 38 %)

 

Refsum like disorder in a Norwegian cosanguineous family

T. Fiskerstrand, MD, PhD, P. Knappskog, PhD, J. Majewski, PhD, R. J. Wanders, PhD, H. Boman, MD, PhD and L. A. Bindoff, MD, PhD .  A novel Refsum-like disorder that maps to chromosome 20.  NEUROLOGY 2009;72:20-27

This slowly progressive disorder starts in childhood with signs of peripheral neuropathy (pes cavus, tendoachilles contracture). Hearing loss and cataract become evident in the third decade. Subsequently, patients develop a disorder of gait due to the combination of ataxia and spasticity, and a pigment retinopathy. While the clinical picture is reminiscent of Refsum disease, affected individuals have normal phytanic and pristanic acid levels in plasma, as well as normal enzymatic activity for -oxidation. We mapped the disease to a 15.96 Mb region on chromosome 20 (20p11.21-q12), containing approximately 200 genes (maximum lod score = 6.3).

Politics of health care reform in NEJM distort reality

The October 29, 2009 issue of the New England Journal of Medicine contains four separate articles on health care issues which, if taken in their entirety, represent the absurdity to which the health care debates in the United States have gone.

The first article-- the best of the four-- describes how much FDA information never reaches clinicians (1). Clinicians and the public rely on the Food and Drug Administration (FDA) for drug and product approvals and denials, and for disseminating accurate information about drugs in their product inserts. I learned that the lengthy, often poorly written and weakly summarized debates about drugs are posted publicly at www.accessdata.fda.gov/scripts/cder/drugsatfda/. The authors cited glaring examples of critical information that somehow was not included in the product labels. Zometa (zoledronic acid, Novartis), used to treat hypercalcemia of malignancy, at the 8 mg dose, caused more renal toxicity and death than the 4 mg dose and was no more effective. Nonetheless, the labelling suggested using the higher dosage "in refractory cases." The product label did not mention increased mortality at the higher dose.

Lunesta (eszopiclone, Sepracor), sold 800 million dollars last year with the help of a direct to consumers marketing campaign. Yet the efficacy data, buried on page 306 of 403, shows patients slept 15 minutes earlier and 37 minutes longer than placebo, with no clinically meaningful improvement in next day alertness or functioning. Similarly, Rozerem (ramelteon), another approved sleep drug, caused younger adults to fall asleep 14 minutes earlier, and older ones 7 minutes earlier, with no improvement on subjective assessments of sleep quality.

The very next article details ways the same government can "further" improve health care. Victor Fuchs (2). advocates incremental rather than radical health care reform. The first of his four proposed reforms is to eliminate employer based health care coverage tax exemptions. The purpose is to raise 200 billion dollars in new revenues, that is taxes, to make the tax system "fairer" since the tax benefit is a regressive tax. He alleges it benefits the wealthy. (Wait a minute-- my practice employs 15 people, who have relatively low incomes and have the same insurance I have. A biller who had breast cancer last year would never have gotten treatment without our comprehensive health insurance). This would allow the creation of insurance exchanges, the second idea, that would, using Fuchs' words, be not as "generous" to "consumers" (actually, sick patients) as the private plans they replace. Supposedly, these exchanges would decrease "broker" costs.

The third, chilling suggestion of Fuchs is the appointment of an "expert" commission to devise changes to the ways Medicare reimburses providers. Fuchs cites "special interests" as blocking the "public good," as a charged way to rally the troops. Again, citing my own practice, with 50 % overhead, a 10 % payment cut equals a 20 % loss of income. Could it be, that by going after providers who have already been sucked dry, Fuchs will drive people out of practice, resulting in fewer providers, thereby raising the cost of care? Fuchs' final idea is an office for technology assessment that would be "quasi-independent." Of whom, I might ask.

The third article-- the last to be reviewed here- describes implementing evidence based medicine in Washington state (3). The state has total authority, except where prohibited by federal statute, to use evidence based methods to assess drugs, devices, surgical procedures, diagnostic tests, imaging procedures, and medical equipment. The author decries the political "pressure" wrought by patients who testify that the benefitted from a technology the state wants to eliminate. Obscenely, the same authors equate pharmaceutical direct to patient marketing with physician "autonomy" and "financial incentive" in ordering tests.
The authors note the "challenges" of this policy, citing the example that thymectomy of myasthenia gravis, used since 1912, has never undergone a rigorous trial. This author will note a few more nonevidence based treatments: penicillin for infection, appendectomy for appendicitis, and burr holes for subdural hematomas of the brain. Are these procedures necessary? Shall the government be in a position to decide? May I be so impudent to suggest satisfaction surveys be returned for all cases of physician assisted suicide?

The assumption of evidence based medicine is that care from one can be generalized to another and is equivalent to another. Evidence is important, and can help us learn how to be better doctors. But, evidence is not the be all and end all. Sometimes doctors have to take the controls from the nurse practitioners and PhD's and make decisions that are in the best interests of the patient. The reasons may not be obvious to the lay public but may be based on sound understanding of pathophysiology. Experience and judgment, absent from these vacuous bureaucratic declarations, still are what most patients seek.





1. Schwartz LM, Woloshin S. Lost in transmission: FDA drug information that never reaches clinicians. N Engl J Med 2009; 361:1717-1720.

2. Fuchs VR. Four health care reforms for 2009. N Engl. J Med 2009; 361: 1720-1722.

3. Franklin GM, Budenholzer BR. Implementing evidence based health policy in Washington State. N Engl J Med 2009; 361:1722-1725.

Idiopathic recurring stupor & narcolepsy automatisms

Several sleep related conditions may mimic and be misdiagnosed as seizures. 80 % of narcoleptics have automatic behavior during sleep. The individual appears awake but is without full awareness. Behavior may be inappropriate and resemble a fugue state.

Idiopathic recurring stupor was described in 1990. The stupors may occur a few times weekly to a few times annually, and last from hours to days. All cases show a widely distributed nonreactive 13-18 hz activity. Flumazeni, a benzodiazepine antagonist, quickly but temporariy reverses the stupor and eeg findings. The culprit is thought to be endogenous benzodiazepines called "enzopines" that act on the GABA A receptor for benzodiazepines. These ligands may alsobe important in learning, memory, hepatic encephalopathy, and panic attacks. CSF enxopine-4 levels are more than 100x higher than in control subjects.

The Larynx for Neurologists

Meyer TK. The Neurologist 2009; 15:313-318. Also points from Rosenfield DB,and Viswanath NS. Neurolaryngology.in Evans R. Diagnostic Testing in Neurology Philadelpia, Saunders, 1999, pp. 223-229.

Larynx functions: phonation, deglutition, airway protection, control of respiration. Laryngeal closure also allows increased abdominal pressure for defection, parturition and stabilization of thorax for heavy lifting.Humans have a lower larynx than grazing animals,helping phonation but more precarious for airway control.

Diseases
Parkinson's disease-- vocal folds are atrophied and bowed with incomplete closure. Patients perceive their own hypophonic speech as of adequate loudness. Voice is also due to bradykinetic efforts from inadequate bellows mechanism (diaphragm and chest wall). Treatment includes bilateral bulking injections to vocal cords to facilitate glottal closure which can be temporary or permanent. Lee Silverman voice technique also helps.

Vocal Cord paralysis. Patient has weak breathy wet voice. It usually occurs due to tumor or surgery. If one vocal cord does not close, can do implant medialization, which will improve voicing and cough in all, and speech in 70 %.

Spasmodic dysphonia-- is a focal dystonia of 2 types. Adductor s.d. is characerized by harsh strangled quality with voice breaks. Abductor s.d is characterized by sustained breathiness with breathy voice breaks. The dystonia is task specific, eg. with breathing, sparing other functions such as swallowing. SD is female predominant with 73 % ADSD, 17% ABSD. Its associated with essential tremor in 30 % and other dystonias in 14 %. Botox is best treatmentfor both types, although the procedure is different for each.



Historical points in dysphonia. Getting stuck,shaking, or improving with alcoholsuggests ET. Trauma can cause dislocated arytenoid cartilage. Pain indicates focal pathology or GERD. Abrupt onset maybe psychogenic. Fluctuations may represent myasthenia.

Signs--

some physical exam tests for conversion disorder

1. Pseudoptosis v. real ptosis. In pseudoptosis, the orbicularis eyebrow brings the eyebrow down. In real ptosis, the frontalis brings the eyebrow up.

2 Hysterical dysphonia. The vocal cords are normal during larygoscopy, cough is normal, articulation in whisper is normal.

3. Monrad Krohn's cough test for hysterical monoparesis. Stands behind patient, grab both lattismus dorsi,ask patient to cough, lats contract prove integrity of brachial plexus.

4. Double crossed arm pull test for hysterical monoparesis. Grab patient's wrists which are crossed across his chest and tell him, "when I say now, pull back as hard as you can." He may pull both sides.

5. "Make a fist " test for psychogenic wrist drop. Wrist elevates with a fist (functional position) or with holding a pencil in posiition.

6. Reversed hands test for functional monoparesis. Interlock hands, ask patient to move finger pointed to.

7. Backward displacement test for psychogenic foot drop. Push patient backwards and see anterior tib dorsiflexors spring into action.

8. Hoover test.One hand under each heel. Ask patient to raise the good leg, and the other one will inadvertently push down in functional patient. If ask patient to push down with both legs, if organically paralyzed he won't if hysterical he might.

9.Raimiste's leg abduction/adduction test for hysterical weakness. Similar to Hoover test for abduction and adduction of legs.

10. Psychogenic visual field deficit with tubular vision, same deficit for near and far Similar, spiral visual field defect may occur with smalllr field with each trial.

Provocative sensory tests pearls

1. Demyer advocates performing position sense tests with the fourth rather than the first digit for greater sensitivity.

2. Pallanesthesia refers to vibratory testing.

3. The directional scratch test on the dorsum of the palm and leg may be superior to other tests of vibratory or position sense (Hankey and Edis, JNNP, 1989). Scratch a line across 2 cm and ask patient if scratch was up or down. If unable to perform accurately (ie, 100 %), repeat with distance systematically increased to make the test quantitative.

4. Two point discrimation with a paper clip can be done touching the patient with one or both ends of the paper clip and asking if patient got one or more than touch. Thresholds for normal two point discrimination in patients more than 7 years old, 2-4 mm on fingertips, 4-6 mm on dorsum of fingers, 8-12 mm on palms, 20-30 mm on dorsum of hands,

Circadian rhythm disorders-- P Zee

AAN talk stuff 2009

1. Keeping time can be regulated at a genetic molecular level with clock genes. This affects both ASPD and DSPD.
2. SCN sends a signal to pineal, which feedbacks to SCN altering circadian rhythms. The main influences on are light, melatonin, and physical activity.
3. Advanced or delayed circadian rhythm disorders occur. Assess with: 7 day eveningness/morningness questionnnaire, sleep diary, actigraphy, core body temperature, melatonin level (24 hour or sleep onset DLMO, clinically available, from saliva) or PSG- ambulatory .
4. Advanced and delayed sleep phase disorder. Rectal body temp usually nadirs 4-6 am, so someone who nadirs at 11 am (college kid?) has a delayed circ disorder. Same patient, melatonin spikes at 1 am whereas for most of us it happens at 9 pm. DSPS has higher rate of BPAD

jet lag pier.acponline.org googlejetlag calculator

east ward trouble falling asleep
west ward trouble staying asleep.

if lags going to Europe, avoid bright light in AM. Speeds up realignment.Needs a week to realign otherwise. Going back west, use melatonin at bedtime at destination.

Other quick hits
REM sleep centers include pons -- perilocus cereleus for atonia, and vestibular nuclei for generation of REM and basal forebrain also plays a role as do other areas.

Sleep pearls, neuromuscular diseases other than ALS

1.  For SMA, do PSG if FVC is less than 65 %.  This is due to kyphoscoliosis and disphragmatic weakness.  Treatment prolongs life length.  The have CSA and OSA.  Annual screening should be done to growth .

2.  Facial issues challenge including short chins and disproportionate midfacial growth causes significant mask leak, and overwhelming constipation causes significant aerophagia.

 

Duchenne's MD

1. When DMD becomes nonambulatory and scoliosis sets in, sleep problems escalate rapidly.  Sleep physicians should by policy statement, be part of team at time of diagnosis, so families understand dyspnea related problems.  When they are in wheelchair, they should have annual PSG's.

2. They have problems with dream sleep. 

3.  An old study showed NIV early in Duchenne's leads to worse outcomes.  The data may be different in the steroid age.

 

Myotonic dystrophy, DM1 subtype.

1.  CTG repeats increase over generations and leads to EDS without strict correlation to muscle issues.  Hypersomnia has primary central reasons.

2.  Sleep fragmentation with short REM latency, decreased Rem abouts and feel tired.

3.  MSLT's resemble narcolepsy.  Not narcolepsy, since no hypnagogic hallucinations, cataplexy, and no abnormal hypocretin abnormalities.

4.  Abnormal cortisol and thyroid rhythms and dropout neurons in raphe nucleus.

5.  RCT's with modafinil have not been completed but treat with stimulants not just sleep disordered breathing

 

Postpolio syndrome

 

Worsening fatigue, severe and incapacitating is the first and prime symptom in PPS.  Its due to multiple problems.  Menopause is very important.  RLS is very common.  Fasciulations are commonly seen in PSG's Inflammation, esp. IL6 , but may not be related to sleep homeostatic mechanisms. 

 

Prior to sending to sleep lab, check a NIF and FVC, and can start NIV without sleep lab referral.

 

Spinal cord injuries

1. Sleep problems include pain, spasms, trouble breathing.

2. Higher injury leads to OSA, 48 % with increased neck thickness with unopposed parasympathetic stimulation and head position  with changes over time.

3.  Use of meds such as baclofen worsen things

4.  Involvement of SCG at C3  affects melatonin.

 

 

4. 

Pearls on sleep disorders in ALS

1. In ALS starting NIV at 70 % predicted FVC preserves life longer than if begun at 50 %. (life extension of 2.7 vs. 1.8 yrs)

2. In ALS CSA and OSA occur early, but OSA drops out, and thoracoabdominal paradox occurs in 30 % and is difficult to test with PSG.

3.  Testing should use multiple modalities including nocturnal O2 sats,  supine FVC, NIF not necessarily PSG. pCO2 more than 45 may be enough.

4.  Bulbar disease especially with FTD is a major risk for nonuse of NIV

5.  Siallorrhea can be treated with benadryl or elavil which also helps sleep and does not mandate non use of NIV

6.  Sleep labs are not set up for ALS patients for many reasons -- lack of facilities for lifts, caregivers, et al.

7.  Classic bilevel devices for central apneas don't account for short shallow breathing in ALS.  Newer pressure control devices that guarantee a longer inspiratory time with a targeted tidal volume are much better.  Need a tidal volume of 8cc/kg IBW.  This used to be achieved by classic ventilator with a mask.

8.  Inappropriate devices such as servo ventilation devices (designed for Cheynes-Stoke breathing) decreased minute ventilation and is not good for ALS.  Autotitrating bilevel devices are designed for use in OSA and are not good in ALS.

9.  Ease of breathing comes from frictional work, with expansion of chest wall, and elastic work, with expansion of lung itself. Lower breaths per minute maximizes elastic work, higher bpm maximizes frictional work, with combined benefit somewhere in the middle with 20 or so bpm.

10.F/ Vt (respiratory rate /tidal volume) is a useful surrogate marker for wob, or work of breathing.  If its less than 33, work of breathing should be OK.    Note that Vt (wob) is proportional to (I-E)/R*T, where (I-E), or the difference between IPAP and EPAP is pressure support, and R  is resistance (which may be increased by kyphoscoliosis eg.) and T is inspiratory time, which turns out to very important in these patients.SLOW deep breathing may be easiest factor to manipulate in these patients.

11. Settings that are important: slow rise time of ventilation in bulbar disease (fast rise time in diaphragmatic disease), inspiratory time of .8 to 1.4 seconds, trigger and cycle adjustments to improved comfort, and tubing sleeve for increased humidity.

Pearls on melatonin and sleep timing Moore

from AAN meeting talks

1. Proposes wakefulness is divided into waking and "default" resting mode with absolutely reliable activation of certain parts of brain during default wakefulness. We do not know what activates the :"default network"

2. Circadian timing is regulated by suprachiasmatic nucleus which inhibits sleep,without which you get random sleep patterns.

3. Retinohypothalamic tract from retina from specific ganglion cells in the photoreceptors that entrain circadian rhythims. They go to SCN via old photopigment called melanopsin with glutamate.

4. VLPO or homestatic drive inhibits ARAS by accumulating NREM sleep via accumulating substances, adenosine and others.

5. So circadian and homestatic drive mechanisms both act on activating activity and regulate sleep.

Presentations of adult onset leukodystrophy

Costello DJ et al. The Neurologist 2009;15:319-328
ALD kids get spastic paraparesis with detrusor instability. Defect is VLFA's ABCD1 mutation. MRI lesion is leukodystrophy starting posteriorly, may enhance partially and be confused with inflammatory disease. Adults may present with neuropsychiatric disease, followed by spasticity, ataxia, seizures, and death. Two thirds of female carriers also develop some sort of progressive myelopathic picture. They may have more pain and be misdiagnosed as having MS or fibromyalgia. Adult cerebral (AC-ALD) is more fulminant than X-ALD.

MLD is aut rec. Presentations in younger patients include disturbed gait, ataxia, quadriplegia, optic atrophy, and peripheral neuropathy, to decerebrate rigidity. In adults, presentation is often neuropsychiatric with misdiagnosis of schizophrenia, or even normal, with neuropscyh testing especially showing problems with visuospatial construction. There are dramatic elevated sulfatides due to arylsulfatase deficiency.

In Krabbe disease, beta galactocerberosidase occurs, is characterized by , in adult form, various motor presentations with progressive cognitive decline, seizures, cortical blindness with 20 % having uniform slowing of nerve conduction studies. Substrate (galactosylceramide) levels are increased but only mildly, but within oligodendrocyte, there are 100 fold increases in psychosine which is cytotoxic and selectively damages oligodendrocytes. Its been described up to age 84. Get posterior predominant involvement, no enhancement.

In Vanishing White matter disease, adult onset, there is cognitive involvement, pseudobulbar palsy, spastic paraparesis, with an important association with ovarian failure, "ovarioleukodystrophy." Its caused by mutations in e1f2b, affects ribosomes and proteins, causes cystic degeneration and rarefaction of the white matter. Clinical features not completely understood, probably is more common than thought.

Alexander disease-- due to mutation in GFAP, causes Rosenthal fibers. Get bulbar and pseudobulbar palsy with white matter abnormalities starting in front.

Canavan disease-- increased NAA in urine, Spectroscopy is good to diagnose this.

Hereditary diffuse leukoencephalopathy with spheroids is almost exclusively diagnosed in adults. Present with deteriorated behavior and personality and seizures. Diagnosis is by tissue.

Pelizaeus Merzbacher is X linked but like ALD carrier females have a forme of disease. Tremor, ataxia, dementia, and progressive spastic paraplegia occur. Mutation on PLP 1 on X q 22 occur. Classic hypomyelinated CNS disorder.

Recessive hypomyelinating leukoencephalopathy (RHL) =PM like disease is a hypomyelinating disease.

others see text, also for Rx

Emerging neuro infections: CHIK, Hendra & Nipah viruses

Ibid (Tyler KT in Arch Neurol 2009)

CHIK virus
infection due to enhanced vector competence. Spread by mosquitoes to humans, togavirus. Abrupt onset fever, joint swelling, myalgia, headache, back pain, and rash. Diagnosis is by CDC IgM and IgG. Rare neurologic cases include encephalitic infections of newborns and elderly.
Other presentations include encephalomyelitis, myeloradiculitis, acute flaccid paralysis (GBS like), encephalopathy and seizures. A mutation in viral envelope dramatically changed infectivity. Endemic travellers to new areas cause infections

Nipah and Hendra viruses.
classification is henipavirus of paramyxovirus. In Australia it first was identified as a highly infectious disease of horses and close human contacts/handlers. Aseptic meningitis and encephalitis occurred in Hendra, a location in Australia.

Nipah virus, closely related, occurred in pig farms in Singapore and Malaysia in 1998. Encephalitis and pneumonitis were common, with a 40 % mortality. The incubation perido was two weeks, with a 3-4 day prodrome. Mortality was 73 %. MRI usually showed multiple small subcortical lesions on T2 and FLAIR images without edema. PEARL- relapsing and delayed onset disease can occur. in 3 % or so average 8 months after first event, with an acute onset the second time. There was an associated systemic vasculitis with thrombosis and parenchymal necrosis in the CNS. Syncytial multinucleated endothelial cells are pathognomomic and occurred in 25 %. A subsequent outbreak in Bangladesh was not associated with pig farms and was shown to be associated with flying foxes and fruit bats with spread through urine of latter. Human to human transmission occurred, including between patients and health care workers.

Monkeypox virus causing neurologic human infection

Tyler KL. Emerging viral infections of the CNS. Part II. Arch Neurol 2009; 66: 1065-74.
Due to exotic pet (mammal ) trade from Africa including Gambian pouched rats, dormouse, and rope squirrels, spread to prairie dogs in the US to humans.

Most common symptoms, 50 percent or more have rash, fever, chills, adenopathy, myalgias, sweats and cough. Rash follows several days later and typically is maculopapular, proceeding through stages with papules, vesicles, and pustules. The rash is centifugal and involves the hands or feet in 80 %, legs or feet in 65 %, head in 6 %, and resembles chicken pox. Unlike chicken pox (and like syphilis and ricketsial infection) there is lymphadenopathy and involvement of the palms of the hands and soles of the feet. Diagnosis is with skin biopsy, PCR, and ELISA.

One six year old developed encephalitis. Diagnosis was made by serum IgM and IgG and CSF IgM, with negative PCR.

rituxan and MG details

Rituximab for myasthenia gravis developing after bone marrow transplant

Neurology - Volume 55, Issue 7 (October 2000)  Rituximab was administered at a dose of 260 mg/m² iv every 7 days for 4 weeks. 6-Methylprednisolone and pyridostigmine were initially maintained at the pre-rituximab dosage of 0.5 mg/kg daily and 4 mg/kg daily. During and after treatment with rituximab the patient was monitored (figure) for muscular strength and performance status using Karnofsky's scale, ARAb titer every other week using a radio receptor assay (Alifax, Hamburg, Germany; cat. no. RE21023/21), CD 20+ lymphocytes (monthly count), serum Ig level, and 6-methylprednisolone and pyridostigmine dose. Rituximab was well tolerated and no complications or toxic effects were registered in the following 5 months of observation. From the fourth week on the performance status improved and ARAb titer decreased. 6-Methylprednisolone and pyridostigmine dosage were gradually tapered to 0.2 mg/kg daily and 3 mg/kg daily at the sixth month of observation, with a performance status of 80 and a substantial reduction of corticosteroid-related symptoms and signs. After treatment with rituximab we observed no changes in serum Ig level; we documented a substantial and prolonged reduction of CD 20+ lymphocyte count (0.2 × 10⁹ /L pre-rituximab, 0.07 × 10⁹ /L and 0.04 × 10⁹ /L 1 and 5 months after the fourth rituximab infusion).

 

Silvestri NJ, Wolfe GI. Rituximab in treatment refractory myasthenia gravis.  JAMA Neurology 2017; 74: 21-23. RTeview. cites Zaja et al 2000 (above);

Lebrun C, Bourg V, Tieulie N, et al. Successful treatment of refractory generalized  myasthenia gravis with Rituximab.  Eur J Neurol 2009: 16: 246-250.  6 patients with refractory disease after thymectomy , got 375 mg/m2 weekly for four weeks then monthly for for two months, then subsequently based on clinical status.  A few patients needed infusions for 1-2 years. All patients ultimately tapered mestinon and prednisone and other drugs. 


Diaz-Manera J, Martinez Hernandez E, Querol L. et al.  Long lasting treatment effect of rituximab in MuSK myasthenia.  Neurology 2012; 78: 189-193 .  17 patients with resistant MG 9defined as failing 3 second line agents. Rituxan was given 375 mg/m2 for four weeks then monthly for two months, then if intereference with ADL's.  All patients with uSK reached minimal manifestation status by 3 months after treatment, and maintained MMS or remitted by 35 months.  Note-- drug seems best suited for MuSK patients. 

Anderson et al.Rituxan in refractory myasthenia gravis: a prospective open-label study with long term followup.. Ann Clin Trans Neurol 2016; 3: 552-555. Refractory MG given Rituxan by abvove protocol or 750 mg/m2 every 2 weeks x 1 month.  3 people got  additional cycles.  At 22 months all patients improved, and pred, IVIG and PE needs decreased. 

One case exists of PML in a MuSK myasthenic patient (Kanth KM, Solórzano GE, Goldman MD. PML in a patient with myasthenia gravis treated with multiple immunosuppressing agents. Neurol Clin Prac. 2016; 6: e17-e19). 

Durability of responseRobeson KR, Kumar A, Keung B et al.  Durability of the rituximab response in acetylcholine receptor autoantibodfy positive myasthenia gravis. JAMA Neurol 2016 : 4190.
After the first cycle, 63 % had sustained remission, 19 % had pharmacological remission and 19 % MMS not requiring treatment.

Of those who discontinued all other forms of therapy, did so at a mean of 8 months (range 1-13) after the last cycle.  9/16 (56 %) relapsed at aa mean of 36 months, but all improved with further immunosuppressive therapy.  All patietns tolerated it well. 

+ four more.

Annot. bibliography B cell function, myasthenia

Zebardast N, Patwa HS, Novella SP, Goldstein JM. Rituximab in the management of refractory myasthenia gravis Muscle Nerve. 2009 Oct 22. (Yale). Studied six refractory patients. Began rituxan 375 mg/m2 weekly for 6 weeks, then 2 treatments every 20-30 days and decreased prednisone. 8 months later received a second course of 5 infusions weekly. A third course of 4 weekly infusions were given 6 months after that. All patients received 4-6 doses of weekly infusion, with subsequent infusions at 6 months if needed.

Nelson RP Jr, Pascuzzi RM, Kessler K, Walsh LE, Faught PP, Ramanuja S, Pescovitz MD, Loehrer PJ Sr. Rituximab for the treatment of thymoma-associated and de novo myasthenia gravis: 3 cases and review. J Clin Neuromuscul Dis. 2009 Jun;10(4):170-7. Review.

Stieglbauer K, Topakian R, Schäffer V, Aichner FT. Rituximab for myasthenia gravis: three case reports and review of the literature.J Neurol Sci. 2009 May 15;280(1-2):120-2. Epub 2009 Mar 9. Review.

Lebrun C, Bourg V, Tieulie N, Thomas P. Successful treatment of refractory generalized myasthenia gravis with rituximab.Eur J Neurol. 2009 Feb;16(2):246-50. Authors followed 6 patients with poor response to immunosuppressive meds. All but one were ACH receptor negative and 3 were anti Musk positive. IVIG did not help. Doses: 375 mg/m2 weekly for 4 weeks After one month steroids were discontinued and anticholinesterase meds decreased. Rituxan cont. every 2 months for six months. Benefit persisted for 2 years of f/u (patient one). Steroids were tapered after the first infusion.

Stübgen JP. B cell-targeted therapy with rituximab and autoimmune neuromuscular disorders. J Neuroimmunol. 2008 Nov 15;204(1-2):1-12. Review.

Illa I, Diaz-Manera J, Rojas-Garcia R, Pradas J, Rey A, Blesa R, Juarez C, Gallardo E.Sustained response to Rituximab in anti-AChR and anti-MuSK positive Myasthenia Gravis patients.J Neuroimmunol. 2008 Sep 15;201-202:90-4. Epub 2008 Jul 23.

Dalakas MC.Invited article: inhibition of B cell functions: implications for neurology.Neurology. 2008 Jun 3;70(23):2252-60. Review.

Pearls on AIDS related neuropathies

see Gonzalez-Duarte A, Robinson-Papp J, Simpson DM. Diagnosis and management of HIV associated neuropathy. Neurol Clinics 2008; 26:821-832
1. Antiretroviral distal sensory neuropathy (ARV-DSP) occurs with didanosin (ddI), zalcitarabine (ddC), stavudine (d4T) plus more recently, adanavir, saquinavir, and ritonavir. It occurs chiefly in first year of treatment or in patients with preexisting neuropathy. Symptoms occur with drug onset and resolve with discontinuation of the drug.
2. DSP due to HIV was formerly associated with high viral load, and low CD4 count and occurs in nearly 100 % at autopsy, and 30-50 percent in clinical practice. Other risk factors are older age, low nadir CD4 count, poor nutrition, coexisting diabetes, and use of neurotoxic drugs (such as antiretrovirals) or alcohol.
3. Of newer drugs, duloxetine is FDA approved for DPNP (diabetic peripheral neuropathy pain) and is under study in HIV DSP. Lamotrigine has been shown to be effective. Elavil and NSIAAD's have not been shown to work.
4. Polyradiculitis is usually pure motor and can be due to CMV, TB, cryptoccosis, and meningeal lymphocytosis. Treponema also has been described. Presentation was usually progressive weakness starting weeks before onset. One case had cervical disease, the rest were lumbar.

Hardscience of concussions

rapid acceleration and deceleration of brain can be estimated as follows
a=(v2-v0)/2sg, easily calculates deceleration based on initial speed v0, final speed v2, and distance travelled s. The result obtained is in terms of g, which is equivalent to 10.73 yards per second (Varney and Roberts 1999). Since the final speed is zero after player stops, formula becomes a= -v0squared/2sg. Then, calculate force applies by F=mg. The number 200g force has been proposed as the amount to cause permanent damage but is not really known.

Brain injury in organized sports

Boxing
Mendez MF. The neuropsychiatric aspects of boxing. Int J Neuropsychiatry Med 25: 249-262, 1995.

Stewart WF, Gordon B, Selnes O. et al. Prospective study of central nervous system function in amateur boxers in the United States. Am. J Epidem 139;573-588, 1994. Bouts fought before 1984 when safety measures were instituted were correlated with neuropsychological impairments.

Football
Abnormalities in sustained attention and visuomotor speed with absent normal practice effects. Preseason baseline assessment by SLAM model is becoming gold standard for concussion assessment and management.
Sideline assessment use SAC,a 5-10 minite measure (McCrea et al, 1996).

Mild traumatic brain injury important articles

JT Barth et al, 1989, 2002 4 yr prospective study of MTBI in college athletics in Sports Laboratory Assessment model (SLAM) with 2300 football players at 10 universities with pre and post neuropsychological assessments. It used a matched control group plus patients as their own control group. After very mild injuries athletes showed a 5-10 day recovery curve for mild cognitive deficits.

Consensus Conference: Rehabilitation of persons with traumatic brain injury . NIH Consensus Development Panel on Rehabilitation of Persons with TBI. JAMA 282:974-983, 1999. Neuropsychological deficits include problems with memory, attention, concentration, executive skills.

headache classification

http://ihs-classification.org/en/02_klassifikation/

Adult onset ataxia telangiectasia (variant AT)

Verhagen MMM, Abdo WF, Willemsen MAAP.  Clinical spectrum of ataxia-telangiectasia in adulthood. Neurology 2009; 73:  430-437 and accompanying editorial.

This important article describes another way adult neurologists cannot completely hide from their brief 3 month training in pediatric neurological diseases that they underwent in training. The summary below focuses on clinical aspects but the article contains genetics information for those interested.

AT is typically an AR childhood disease that one can read about in a 1980 edition of Adams and Victor.  Variant AT occurs in older adults as a forme fruste perhaps of the pediatrics form. It is described in about 13 patients.  Patients usually had young onset movement disorders, either choreoathetosis or resting tremor.  Distal muscle weakness occurred in one patient.  By age 27 patients began to experience progressive cerebellar atrophy with eventual development of dysarthria in all, continued movement disorders, nystagmus, dystonias and oculomotor apraxias.  EMG/NCS showed either anterior horn cell involvement or sensorimotor polyneuropathy.  Cerebellar atrophy on imaging affected vermis primarily. 

Minimal  telangiectasias of either eye or skin occurred in variant form.  Lung function was normal.  Four of 13 developed malignancies including ALL, ectopic pituitary tumor, and breast cancer.  Alpha feto protein levels were markedly elevated in all patients  to ten to fifty times normal, although this is still less than in classic AT. Ig deficiencies occurred in only one patient and were of minor degree. 

Adult patients with classic AT also exist and present with cerebellar ataxia, ocular telangiectasia, immunodeficiency, rearrangement of chromosomes 7 and 14, X ray hypersensitivity and elevated alpha feto protein levels.  Patients were all wheelchair bound, had growth retardation, endocrinopathy including type 2 DM, diminished secondary sexual characteristics, restrictive lung disease, and more cancer especially lymphoproliferative diseases.  Defect is in DNA repair. 

Alpha fetoprotein appears to be good screening tool.

MGUS: significant beyond hematology

Vanderschueren SW, Mylle M, Dierickx D et al. Monoclonal gammopathy of undetermined significance: significant beyong hematology. Mayo Clin Proc. 2009; 84:842-847.

MGUS is found in 3% of patients older than 50, 5% older than 70, in 7 % of patients seeking medical evaluation, and converts to myeloma at rate of one percent per year. Authors present five OTHER associations of MGUS that are commonly underrecognized.
1. Acquired C1 inhibitor deficiency. should be suspected in patients with repetitive often stereotypic episodes of angioedema, with no urticaria or pruritus or family history, & in pts with recurrent acute abdomen with normal CRP and low C4 levels. Hereditary form occurs in first two decades usually, acquired forms in elderly patients with MGUS in up to 40 % of cases (IgG, IgM or IgA). In acquired forms C1q levels are low due to consumption. Acute prophylaxis can be done with antifibrinolytics eg. transexamic acid or danazol, and acutely FFP has variable success.
2. Systemic capillary leak syndrome should be suspected in patients with repetitive hypovolemic shock, capillary leak and hemoconcentration (in case report, HB went from 15 to 23 in one day). Attacks characterized by prodrome malaise, fatigue, OH, polydipsia, palpebral edema, last 1 to several days and have high fluid requirements during an attack. MGUS usually IgG is typically present. Intestinal edema, ascites, muscular edema, pleural and pericardia effusions occur, may have compartment syndrome. Terbutaline, theophylline, and IVIG are used to treat.
3. Acquired von Willebrand syndrome-- uncommon condition occurs in elderly patietns with no history or family history of bleeding, with MGUS in 50-60 %. Desmopressin works transiently. High dose IVIG has been used. Suspect with mucocutaneous or postop bleeding.
4. Schnitzler syndrome-- heralded by repetitive fevers and chronic, initially nonpruritic urticaria. CRP and ESR are typically very high. MGUS is usually M type. Anakinra, an IL1 antagonist shows promise.
5. Scleromyxedema-- characterized by typical skin eruption and visceral or repetitive neurologic involvement. Case reported of 39 yo man with episodic confusion preceded by flu like illness proceeding to status epilepticus and prolonged postictal coma. Over weeks, appeared erythematous plaques on face and skin creases over glabella , confirmed with biopsy to be scleromyxedema. Tx was plasmapx, IVIG, dexamethasone, autologous stem cell, thalidomide. Its caused by hyaluronic acid deposition in superficial dermis and production of MGUS usually IgA. Also called papular mucinosis and generalized lichen myxedematosus. Occurs in patients usually 30-50 , may include MI as well. Also called dermatoneural syndrome.