Pearls for Multiple System Atrophy

Neurologist July 2008 14L224-237 authors Bhidayasiri R, Ling H.

MSA encompasses sporadic OPCA (MSA-C) and SND (OPC-P) with predominant Parkinsonism and both types including dysautonomia. Tremor is common but not classic pill rolling tremor. Impotence in men and urge incontinence in women are nearly universal, postural hypotension occurs in 2/3 and syncopal episodes in 15 %. Stridor and respiratory insufficiency may be presenting signs. 29 % respond to levodopa AT SOME POINT.

Red flags suggestive of MSA include early severe autonomic dysfunction, spontaneous or L dopa induced orofacial dyskinesias, which may even resemble risus sardonica in tetanus. Pisa syndrome is a form of axial dystonia, and camptocormia is forward flexion of the trunk. These are not specific and may be seen in PD. Disproportionate anterocollis may occur at any point of the disease, although rare, and botox for this can worsen dysphagia; this is a red flag. So is minipolymyoclonus, which is postural or stimulus sensitive small amplitude nonrhythmic movements of a few fingers or the whole hand. Dysarthria may be diagnostic, with a quivering, croaky strained element "reminiscent of myoclonic speech." (cit Arch Neurol 1996 53:545-548). Nighttime stridor is helpful diagnostically but poor prognostically and may present as laryngeal paresis. Sleep apnea, the "cold hand sign" and emotional incontinence comprise the other red flags.

groupings of "red flags: show six categories  early instability, rapid progression, abnormal postures, bulbar dysfunction, respiratory dysfunction, emotional incontinence.  Presence of two or more categories had high sensitivity (84 % ) and specificity (98%). see Hughes et al.  JNNP 1992; 55:181-184.

Exclusion criteria also are important, including age under 30, positive family history of MSA (PD is "OK"), frank dementia at onset, and eye movement abnormalities suggestive of PSP or CBGD.

The Quinn criteria for possible, probable and definite MSA are reviewed. International Consensus Conference Criteria of the AAN are considered better. See NEJM 2004; 351:912-924 (Case Records of the MGH).

MRI signs include atrophy of the cerebellar vermis, ponsmiddle cerebellar peduncles and lower brainstem. Signal change in the pons may resemble a "hot cross bun" (Catholics may understand this). In MSA-P, patients may have putamenal atrophy, with slit like void signal (black reflecting gliosis) which is sensitive but not specific, but is sensitive and specific if coupled with hyperintense T2 signal in the putamen. For a PD/MSA algorithm, see Arch Neurol 2002; 59:835-842). Onuf's nucleus degenerates which accounts for bladder problems. Pathologic confirmation is made by finding of alpah synuclein positive GCI's composed of misfolded alpah synuclein.

Pearls for treatment include, use of levodopa in many, the benefits of paxil 90 in one trial for motor function, botox of submandibular glands for drooling, and into adductor muscles for stridor, with concerns as above for other uses of botox. PT/OT/ST/ gait training and assistive devices are useful. Treatment of dysautonomic can include, if needed, avoiding large meal, alcohol, straining, certain meds; elastic stockings, bed tilt up at night. Drugs used for orthostasis include florinef, midodrine, desmopressin, octeotride, and eryuthorpoeitin. NGB can be treated with intermittent catheterisation, anticholinergics if detrusor hyperreflexia exists, suprapubic vibration devices, alpha adrenergic receptor antagonists, but NOT surgery. Beware of sildafenil for impotence due to hypotension. Macrogol 3350 for chronic constipation is safe and effective, increasing water content of stools. CPAP, may be needed, tracheostomy may be needed but also may be fatal due to hypercapnia. CPAP mat be contra-indicated if the epiglottis is floppy (Neurology 2011; 76:1841)

periictal water drinking localizes as does kissing epilepsy

Peri-ictal water drinking lateralizes seizure onset to the nondominant temporal lobe

E. Trinka, MD, G. Walser, MD, I. Unterberger, MD, G. Luef, MD, T. Benke, MD, L. Bartha, PhD, M. Ortler, MD and G. Bauer, MD

From the Universitätskliniken für Neurologie, Innsbruck (Drs. Trinka, Walser, Unterberger, Luef, Benke, Bartha, and Bauer), and Universitätsklinik für Neurochirurgie (Dr. Ortler), Innsbruck, Austria.

Address correspondence and reprint requests to Eugen Trinka, MD, Universitätsklinik für Neurologie, Innsbruck, Anichstrasse 35, A-6020 Innsbruck, Austria; e-mail: eugen.trinka@uklibk.ac.at

The authors describe seven patients with medically refractory temporal lobe epilepsy whose seizures were associated with peri-ictal water drinking behavior. Presurgical evaluation, including video-EEG monitoring, MRI, SPECT, and neuropsychological testing, revealed a seizure onset in the nondominant temporal lobe. All patients had an excellent outcome after epilepsy surgery. Peri-ictal water  drinking may represent a lateralizing sign indicating seizure onset in the nondominant temporal lobe.

^{AAN 2010 PO5:210
Ictal kissing is a release phenomenon in nondominant temporal lobe epilepsy. 3 patients with ictal kissing were all righthanded women with longstanding right TLE.  Its occurrence to environmental cues suggests its a release phenomenon rather than an ictal event}

ictal eye closure = pseudoseizures

Ictal eye closure is a reliable indicator for psychogenic nonepileptic seizures

Steve S. Chung, MD, Paula Gerber, MD and Kristin A. Kirlin, PhD

From the Departments of Neurology (S.S.C., P.G.) and Clinical Neuropsychology (K.A.K.), Barrow Neurological Institute, St. Joseph's Hospital and Medical Center, Phoenix, AZ.

Address correspondence and reprint requests to Dr. Steve S. Chung, Department of Neurology, 500 West Thomas Road, Suite 300, Phoenix, AZ 85013; e-mail: sschung@chw.edu

Using data from video-EEG monitoring, the authors studied whether ictal eye closure was a reliable indicator of psychogenic nonepileptic seizures (PNES). Among the 52 patients with PNES, 50 consistently closed their eyes, while 152 of the 156 patients with epileptic seizures (ES) opened their eyes during seizures. These findings suggest that ictal eye closure is a highly reliable indicator for PNES, while ictal eye opening is an indicator of ES.

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Photic seizures

"Pokemon incident" showed alternating red and blue light each for 12 hz caused seizures in japanese kids. 1 seizure per 10000 kids watching (as opposed to 1-3 % photosensitive) but more have sensitivity to other stimuli. Most such kids had no knowledge they had prior seizures. More females by percentage but more males by number, more young, usually generalized but sometimes focal. Brightness, esp over 100 lux; flash rate over 5-30, must go on for more than a half second and fill at least half the field, colors red flashing are the worst (advise blue sunglasses); especially moving vertical bars (stripes), and viewer factors such as covering an eye, tired, meds, exposure time. More TV seizures in Europe because there is higher flicker rate in Europe.

Posterior reversible leukoencephalopathy s (PRES) PEARLS

First described at Tufts University Department of Neurology, 1996, by Judy Hinchey, Claudia Chaves et al.

1. Associations:
cytotoxic drugs (steroids, mtx, tacrolimus, cyclosporine, imuran)
hypertension
glomerulonephritis
porphyria
pheochromocytoma
malignant hypertension
eclampsia
NMO (neuromyelitis optica or NMO spectrum disorder)
autoimmune disease
sepsis
TTP
multiple organ dysfunction especially renal
2.  MRI pearls
--spares the calcarine cortex whereas stroke affects midline calcarine cortex
--may also affect frontal lobes, basal ganglia, brainstem, cerebellum
--no relationship between clinical severity, association, and location of lesions


3. treatment
remove drug
mag sulfate
control blood pressure

4 Review article Mayo Clin Proceedings May 2010 85:5: 427-432
120 cases in 113 patients over several years
-- may self resolve, but substantial Mortality and morbidity due to potential complications including massive infarction, hemorrhage, status epilepticus.
--hypertension present in 74 percent, but only 46 % of those had a history of chronic hypertension
--renal failure present in 57 %, but only half of those had chronic renal insufficiency
--clinical presentations included seizures in 74 % (partial or generalized, only rarely with history of seizures), 18 % with status epilepticus, 28 % with encephalopathy, 26 % with headaches, and 20 % with visual disturbances
-- Autoimmune disease was present in 45 %, of whom three fourths were women.These included TTP (27 %), SLE (18 %), hypothyroid (10 %), scleroderma (6%), Crohn's disease (6 %), ulcerative colitis or sclerosing cholangitis (4 %), RA (4%), DM ( 4%), and 1 patient each or 2 % for Graves' disease,  Hashimoto's thyroiditis, APL syndrome, anti glomerular basement disease, autoimmune hepatitis, polyarteritis nodosa, thromboangitis obliterans, polyglandular autoimmune syndrome, Sjogren's, gfrnulomatous interstitial nephritis, NMO
-- Of patients with autoimmune disease, 65 % had cerebellar involvement, and majority of septic patients had involvement of the cerebrum.
-- transplant and chemo and pediatric populations not represented in above article

Clinical Care of ALS patients

based on Radunovic Am Mitsumoto H, Leight PN Review article in Lancet Neurology October 2007. Based on the idea that basic medical management is underutilized. Major points:
1. Diagnosis (correct diagnosis) necessitates evaluation initially including brain and spine imaging (most of the time), CXR, lab tests, EMG. Use El Esocorial criteria http://www.wfnals.org/guidelines/1998elescorial/elescorial1998criteria.htm. Prior links to other important ALS information including EMG criteria, mimics and others. Dx is hardest with only UMN or only LMN signs. Mean survival is 30 months from diagnosis. Long survivors were not necessarily the ones taking riluzole. The ALS Functional Rating Scale http://www.outcomes-umassmed.org/als/alsscale.cfm and vital capacity are the most useful clinical measures.

Authors emphasize team approach and palliative care. Some of the treatments especially medicines are well known and obvious and are not reblogged. Some "tricks" are listed below.

excess saliva-- non medicine treatments include home suction, dark grape juice, sugar free citrus lozenges, nebulizers, botox, parotid radiation, steam inhalers. Medicines include elavil glycopyrrholate, hyoscine.

Excess broncial secretions-- propanolol, metoprolol, carbocysteine?, assisted cough insufflator/exsufflator. rehydration, pineapple or papaya juice, butter, decreased intake dairy products, alcohol and caffeine.

excess yawning-- baclofen

laryngospasm-- baclofen

emotional lability-- TCA's, Sinemet, dextromethrophan and quinidine

Noninvasive ventilation at onset of respiratory insufficiency among patients with no/moderate bulbar dysfunction improves survival. It also improves quality of life. Initiate when FVC is less than 40 % that of predicted and it doubles survival. Authors state measure of sniff nasal pressure is better than FVC and that measure of 32 % (= 25 cm H2O) or less predicts respiratory failure whereas FVC of 40-50 % does not do so as well . SNP less than 40 cm H20 predict survival. Other measures such as inspir/expir mouth pressures, PSM, sniff transdiaphragmatic pressureand diaph EMG provide more info. Begin noninvasive ventilation when patient has nocturnal hypoventilation including dyspnea and orthopnea. , low SNP, nocturnal desaturation (< 90 % for more than 5% of sleep) or AM hypercapnia more than 6.5 kPa.

Discuss tracheotomy with patient in advance. It prolongs life but is "beyond means" of many patients, who might not want it. Lorazepan, morphine are OK but not oxygen which (unless patient is hypoxic) worsens mouth dryness and hypercapnia.

Nutrition can be assessed with dietary history, BMI, and weight. Enteric feeding can be considered with more than ten percent weight loss. Swallow studies, assessment of choking, food texture, drooling, meal duration , fatigue, video studies to assess silent aspiration. Use thickeners, lip seal, tongue exercises, chin tuck flexing neck forward when swallowing) with eating smaller more frequent meals with enough calories.

Authors emphasize role of hospice, grief couselling for families.

new seizure drugs coming up

Drugs. 2008;68(14):1925-39.

Related Articles, Links

Pharmacological management of epilepsy : recent advances and future prospects.

Johannessen Landmark C, Johannessen SI.

Department of Pharmacy, Faculty of Health Sciences, Oslo University College, Oslo, Norway.

There is still a need for new antiepileptic drugs (AEDs) as the clinical efficacy, tolerability, toxicity or pharmacokinetic properties of existing AEDs may not be satisfactory. One new AED has recently been approved (rufinamide in 2007) and six others are in late-stage development (phase III and onwards) [brivaracetam, carisbamate, eslicarbazepine, lacosamide, retigabine and stiripentol]. The purpose of this review is to provide updated data on proposed mechanisms of action, efficacy and tolerability on these new AEDs, and to discuss the rationale for their development and possible advantages compared with existing treatment, based on recent publications and MEDLINE searches.Rufinamide, brivaracetam and stiripentol have been given the status of orphan drugs. Rufinamide was approved in Europe in 2007 for the use in Lennox-Gastaut syndrome. Brivaracetam has gained orphan status for development in progressive and symptomatic myoclonic seizures in Europe and the US, respectively. Stiripentol has gained orphan status in children with Dravet's syndrome and pharmaco-resistant epilepsy. All of these drugs demonstrate efficacy as adjunctive therapy in partial seizures. Three of the drugs are derivatives of existing AEDs: brivaracetam is a derivative of levetiracetam with improved affinity for the target molecule; carisbamate is a derivative of felbamate with improved tolerability; and eslicarbazepine is a derivative of carbamazepine with less interaction potential and no auto-induction. Lacosamide, retigabine, rufinamide and stiripentol are new compounds, unrelated to other AEDs.Further investigation and development of new broad-spectrum drugs is important for improved treatment of patients with epilepsy and other neurological and psychiatric disorders.

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Misc. Signs of drug use/withdrawal

1.  tachycardia
2.  hyperthermia
3.  purulent drainage from nares with erosions (think cocaine)
4.  pop marks on skin
5.  hear murmur/ other signs of SBE (see Harrison's textbook for list)

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Differential of delirium with quadriparesis/paraparesis

1.  central pontine myelinolysis
2.  progressive multifocal leukoencephalopathy
3.  acute disseminated encephalomyelitis
4.  Cobalamin deficiency (have not seen like this)
5.  cryptococcal meningitis
6.  critical illness neuromyopathy
7.  new onset myasthenia gravis, unsuspected, postoperative

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Porphyria pearls

taken from NEJM CPC 2008; 358;2813-2825

case (abbreviated severely). 57 year old woman was admitted with abdominal pain and weakness. She had just had bariatric surgery for obesity. MRI showed changes of posterior reversible leuokoencephalopathy syndrome (turns out it occurs in porphyria). She had had intermittent dark urine and tachycardia.

Patient developed numbness, weakness and tingling in lower extremities, fell while walking and had an episode of confusion and urinary incontinence. She quickly (within days) could not stand or sit independently, became incontinent of stool with numbness and tingling along her body. She had 4/5 strength throughout, with fatigueing and absent reflexes. Sensation was normal. CSF showed normal glucose, protein and no cells. EMG showed an acute motor neuropathy. Strength deteriorated to 0-3/5, worse in proximal than distal legs. There was no response to IVIG.

Pearls-- factors for porphyria in this case were recurrent severe abdominal pain, dark or reddish urine, arterial hypertension, tachycardia and constipation. The diagnostic test in 5-ALA and PBG in urine or serum. A rapid test is the PBG in urine (Hoesch or Watson-Schwartz reaction). Key is diagnose porphyria first then type it. (False positives in 5-ALA are lead posioning and hereditary tyrosinemia type I).

Most types are inherited but the most common type, porphyria cutanea tarda is acquired, associated with liver disease and iron overload. Of 4 types, any may present with neurovisceral presentation esp colicky abdominal pain, and hereditary coproporphyria and variegate porphyria can also present with cutaneous features. Attacks are likely precipitated by adverse effects of excess ALA which is structurally similar to GABA. Starvation, poor CH2O/ energy intake, drugs, alcohol, smoking, infections and stress can ppt. In this case the negative energy balance with surgery caused up regulation of hepatic ALA synthase 1, due to loss of CH2O repression of rate controlling enzyme for heme synthesis in the liver. Other "bad " drugs in this case were phenytoin, tramadol and bactrim. Sulfonamides and barbiturates are also "bad." So is progesterone (which is why postpubertal women are more susceptible). The treatment is i-v heme. It can prevent reversible axonal death. Prognosis is slow and incomplete recovery. Noted also in this case wwre blisters in sun exposed parts of the body. She had variegate porphyria.

MoCa test for cognitive impairment

The MoCA test is an alternative to the MMSE which has had its share of problems.  Link for information  http://www.mocatest.org/

 

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Insulinoma mimicking seizure

Bazil CW, Pack A Insulinoma presenting as a seizure disorder. Neurology 2001; 56:817-818.

This rare disease mimicking a common disease needs to be added to the knowledge of doctors diagnosing individuals with various "spells." A 45 year old woman had troubel with panic attacks, inability to focus, tongue/limb tingling, perception of yellow spots and cold sweat. She later developed episodic unresponsiveness and jerking. Waxing and waning irda and polymorphic delta was seen on eeg, without interictal discharges, and the patient was felt to have pseudoseizures. A low glucose of 55 was found, islet cell tumors of the pancrease were found and removed and the patient took diazoxide with improvement.

Insulinoma usually includes nonspecific symptoms such as dizziness, apathy, headache and confusion. It is rare. affecting at most 5 per million.

Neuropsychiatric Profiles of Patients with Insulinomas; Ding Y, Wang S, Liu J, Yang Y, Liu Z, Li J, Zhang B, Chen Y, Ding M; European Neurology 63 (1), 48-51 (Dec 2009)
A review of 42 patients with insulinoma was undertaken, showing that many went undiagnosed for up to five years with neurologic and neuropsychiatric symptoms. 12 were misdiagnosed as epilepsy with eeg findings. Others received psychiatric diagnoses. Clinical presentation was usually confusion, convulsions and visual disturbance.

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manage carotid body tumor

fromClinical Neurology News:

Resection Remains Best Treatment for Carotid Body Tumors
PATRICE WENDLING (Chicago Bureau)
Article Outline
• Skip Angiography, and Other Surgical Pearls
• Copyright
CHICAGO — Surgical resection remains the treatment of choice for carotid body tumors, as presented in a review of 88 patients at one center.
Radiation therapy and chemotherapy are unsuitable alternatives because these rare tumors are too slow growing, and radiation exposes the carotid arteries to radiation arteritis, accelerated atherosclerosis, and even necrosis, Dr. Thomas A. Whitehill said at a vascular surgery symposium sponsored by Northwestern University.
Preoperative percutaneous tumor embolization has been tried with mixed results, but can be an important adjunct when treating select patients with large tumors (greater than 6 cm). There has been one report of a successful use of covered stents to facilitate resection (J. Vasc. Surg. 2003;38:389–91).
The malignancy rate for carotid body tumors is hard to define because there are no reliable histologic markers, but is thought to range from 2% to 5%, he said. Even if benign on histologic exam, all tumors, once discovered, should be surgically removed because they will ultimately wrap around the internal and external carotid arteries, erode into the base of the skull, and entrap neighboring cranial nerves. Increasing size also can interfere with speech, swallowing, and respiration, said Dr. Whitehill of the vascular surgery division of University of Colorado Health Science Center, Denver.
From 1993 to 2007, Dr. Whitehill and colleagues surgically resected 88 Shamblin classification II or III carotid body tumors, with an average diameter of 10.4 cm (range 5–16 cm). The patients ranged in age from 30 to 40 years.
Surgery time ranged from 4 to 14 hours, with an average blood loss of 375 mL (range 50–1800 mL). An internal carotid artery (ICA) resection bypass was performed in three patients, and ICA ligation in none.
Complications were relatively low, Dr. Whitehill said, and included cranial nerve IX neuropraxia (4%) or injury (1%), cranial nerve XII neuropraxia (30%), and superior laryngeal nerve injury (10%). There were no strokes or deaths.
Surgical advances and the widespread use of CT and MRI have decreased the overall risk of postoperative stroke over the past 25 years from about 30% to less than 2%, although the incidence of cranial nerve injury remains high at 15%–35%, he said.
Skip Angiography, and Other Surgical Pearls
Dr. Thomas A. Whitehill offered tips for carotid body tumors.
▸ Skip the angiography suite when making the diagnosis, and focus on CT imaging, preferably axial cuts rather than reconstructions. MRI may be slightly better at evaluating distant, metastatic deposits at the skull base.
▸ A nerve stimulator may be useful for preoperative identification of the cranial nerve.
▸ Do preoperative vocal cord and speech evaluations.
▸ Consider serial embolization in patients who are too old or have too many comorbidities to tolerate surgery.
▸ On a side CT view, draw a line between the mastoid tip and the angle of the mandible to get an idea of how high an exposure is needed and to help with preoperative planning.
▸ Utilize nasotracheal intubation in most patients, as it provides greater mobility with the mandible when resecting large tumors.
▸ In high access cases, mobilize the parotid gland anteriorly, up to the level of the facial nerve.
▸ Gain vascular control, if possible, and mobilize the tumor circumferentially to assess the extent of disease.
▸ Resect the tumor from proximal to distal.
▸ Fine mosquito clamp dissection and 3–0 or 4–0 silk ligation can give the best hemostasis.
▸ Send all suspicious lymph nodes for frozen permanent sections.
▸ Rather than using maxillomandibular arch bar fixation to obtain mandibular subluxation, consider interdental cross-wiring between the maxilla and mandible using bicuspids in dentate patients and Steinmann pins in patients with no teeth.
▸ For very distal tumors, cutting the digastric muscle will get you within 2 cm of the skull base.
▸ For large tumors, ligating the external carotid artery near its takeoff provides greater mobility.
▸ Avoid ligation of the internal carotid artery.
▸ If a tumor is 6 cm or more in diameter, consider preoperative embolization.
▸ Pushing the tumor completely through the bifurcation or pulling it anteriorly through the bifurcation may improve exposure angles and ease dissection.
▸ Take your time after the tumor is cleared of the two carotid arteries. The posterior surface and medial side of the tumor still must be separated from the deeper parapharyngeal tissues. Haste at this stage can result in the superior or inferior laryngeal nerves being transected or medial pharyngeal injuries, causing substantial swelling and neck pain in patients.

Typing PSP

"The postmortem room has become the temple of truth" (Donald Calne, re PSP) (Neurology 2008)Current nomenclature"Richardson disease" corresponds with initial descriptions. There is a gradual onset of postural instability and falls within the first two years, with vertical supranuclear gaze palsy, a frontal dysexecutive syndrome, rigidity and bradykinesia that is not responsive to leveodopa, and a life expectancy of six years.A second milder group at pm (post-mortem) have PSP tau pathology that is more restricted and less severe are called PSP-P (PSP-parkinsonism). They have assymmetric bradykinesia of the limbs, an initial response to levodopa, tremor and limb dystonia without early falls, eye movement problems, or cognitive dysfunction. Most patients with "atypical PSP" are in this category. The third rarer category is pure akinesia with gait freezing (PAGF). There is gradual onset of unsteady or slow gait and hypophonia progressing to gair freezing and start hesitation, without limb rigidity or tremor. There is no response to levodopa and there is no dementia or opthalmoplegia in the first five years. In types 2 and 3 the median duration of the disease is around ten years. Other patients with similar tau-PSP pathology present with corticobasal ganglionic degeneration, progressive nonfluent aphasia, or apraxia of speech. References up to date:Williams DR, de Silva R, Pavour DC et al. Characteristics of two distinct clinical phenotypes in pathologically proven progressive supranuclear palsy: Richardson' syndrome and PSP - parkinsonism. Brain 2005; 128:1247-1258.Williams DR, Holton JL, Strand C. et al. Pathological tau burden and distribution distinguishes progressive supranuclear palsy-parkinsonism from Richardson's syndrome. Brain 2007; 130: 1566-1576.Mizusawa H, Mochizuki A , Ohkoshi N, et al. Progressive supranuclear palsy presenting with pure akinesia. Adv Neurol 1993; 60: 618-621.Josephs KA, Duffy JR, Strand EA et al. Clinicopathological and imaging correlates of progressive aphasia and apraxia of speech. Brain 2006; 129: April 13.Tsuboi Y, Josephs KA, Boeve BF et al. Increased tau burden in the cortices of progressive supranuclear palsy presenting with corticobasal syndrome. Mov Disord 2005; 20: 982-988.

Limbic encephalitis : An expanding concept: teratomas and "things"

Graus F, Saiz A. Neurology 2008; 70: 500-501 (editorial) . Also see http://dementianotes.blogspot.com/2008/06/vgkc-autoantibodies-mimicking-cjd.html re VGKC antibodies in particular.

A syndrome of encephalitis in 12 women with teratomas of the ovary follows a predictable clinical pattern. A prodromal fever, is followed in a few days by a prominent psychiatric syndrome or short term memory loss, then, seizures, then progressive unresponsiveness (catatonia like stage) , dyskinesias, autonomic instability, and central hypoventilation. ICU support for weeks or longer may be necessary, and patients recover generally after tumor removal or immunotherapy (pheresis or IVIG). MRI is usually negative (9/12). All patients had CSF and serum antibodies against components of NMDA receptor (NMDAR) especially 2 subunits NR1/NR2). These particular patients express NR1, which is ubiquitously expressed in brain, but in these patients distributes with NR2 (basal forebrain) and disappears with treatment. This contrasts with NR2B which is seen in Rasmussen's excephalitis, refractory epilepsy, and stroke. In neuropsych lupus, this epitype leads to apoptosis.

Iizuka et al. now describe this epitype in Japanese juvenile non-herpetic encephalitis (with NMDAR). They emphasize the abnormal movements, especially orolingual after initial psychiatric syndrome and catatonic like state. These patients can reverse even after long periods of ventilator dependence.



Update  pearls for NMDAR  from Neurology 2014; 82: 550-551 (editorial)

1.  Tests for:  CSF with HEK cells expressing GluN1/2 subunuts of the NMDAR cell based assay. or serum.  with serum there is a 15 % false negative/positive result

2.  Adult men more often presented with seizures (18 %) whereas women more oftenpresent with behavior/psych symptoms  

3.  Among women, 41 % had tumors, all ovarian teratomas.  Among men only one had a tumor likely unrelated schwannoma. 

Rosai-Dorfman disease presenting with widespread intracranial and spinal involvement

Kidd DP, Revesa T, Miller NR. Neurology 2006; 67:1551-1555.
Disease is also known as sinus histiocytosis with masssive lymphadenopathy. It has a much more benign prognosis than histiocytosis X. A registry published in 1990 of 238 patients showed that of 238 patients, 49 had a lasting remission, 165 had stable disease not requiring treatment, and 21 had died 4 of the disease. It presents in the third to fifth decade with cervical lymphadenopathy often preceded by a viral infection, with elevated ESR and polyclonal gammopathy. Steroids and/or XRT is used for treatment. Authors present two neurologic cases. One mimicked a sellar meningioma with loss of vision, hearing and smell. A gallium scan and chest CT showed chest lesions. The other presented with four months of progressive visual loss. Only 4 % have neurologic involvement (8 patients) five with spinal dural based lesions, three with intracranial epidural lesions.

My question: cases did not describe cervical adenopathy so why was diagnosis made?

Unusual sources of lead leading to intoxication

Lead was an ingredient of antibacterial ointments until the 20th century and are still sold in rural Switzerland. Traditional remedies including Asian plant products may be contaminated. Beauty ointments may be a culprit including lip balms (Fluri et al. Neurology 69:929 2007).

Serum, not urine lead levels should be checked and porphoryns may be elevated. MRI may show hyperintensity in the basal ganglia. Encephalopathy and motor neuropathy both can occur in adult intoxications.

Bacterial and fungal meningitis in patients with cancer

Safdieh JE, Mead PA, Sepkowitz KA et al. Neurology 2008; 943-947. High points-- only five percent of cases had the triad of fever, nuchal rigidity and mental status changes. VP shunt patients usually presented with mental status changes. Most patients had had prior neurosurgery. organisms included more gram positive infections and a smattering of diverse other organisms. CSF response was often muted.

Differential diagnosis of cervical radiculopathy

1) Peripheral nerve entrapment (eg CTS)- see positive Phalen's and Tinel's sign, typical distribution, abnormal nerve conduction studies v. normal in cervical radiculopathy

2)Rotator cuff abnormal-- pain in shoulder or arm, rarely below elbow, worse with shoulder movements, normal sensation and reflexes.

3) Acute brachial plexitis-- (Parsonage Turner)-- see pain in neck shoulder and arm followed within days to weeks by weakness especially in C5-6 region as pain recedes (whereas in radiculopathy pain and weakness coincide).

4) Thoracic outlet syndrome-- Pain in shoulder and arm, intermittent paresthesia, C8-T1 symptoms (rare in radiculopathy), reproduction with provocative tests including Roo's test (rapid flexion and extension of fingers with arms abducted at 90 degrees and externally rotated 90 degrees), normal neuro exam, decreased radial pulse with vascular compression (rare) and usually normal NCS.

5) Herpes zoster-- neuropathic pain in dermatomal distribution followed by vesicular rash.

6) Pancoast syndrome-- Pain in shoulder/arm due to plexus compression, paresthesia is in C8-T1 distribution (intrinsic hand muscles), ipsilateral ptosis, miosis, and anhidrosis.

7) Sympathetic mediated syndromes-- pain and burning in arm with swelling, hyperesthesisa, allodynia, and vasomotor changes (temperature and color) with normal neurologic examination.

8) Referred somatic pain from neck-- such as discs, joints, usually segmental C5-6 felt in posterior neck and supraspinatus fossa, normal neuro exam.

9) SUNCT/SUNA syndromes with pain in cervical region

Cervical radiculopathy

Carette S, Phil M, Fehlings MG. Clinical practice. NEJM 2005; 353:392-399.

The etiology in 70-75% is encroachment of the foramen due to cervical spondylosis or other cause of degeneration, whereas HNP is much less frequent (20-25 %) and tumors and other causes even less frequent. Pain occurs only if the dorsal root ganglion (DRG) is compressed. Hypoxia of the nerve root and DRG exacerbates the pain. Inflammatory mediators including MMP's, PGE2, IL6 and NO. Nonsurgical management resolution correlates with imaging improvement.

Neck and arm pain predominate. Sensory symptoms (burning, tingling) follow a dermatomal distribution, but pain follows a myotomal pattern. C7 pain for example includes radicular pain to forearm, and N/T to the third digit. Pain is relieved by looking to opposite contralateral side and holding hand on top of the hand and exacerbated by turning the head towards the pain. Red flags including systemic signs of illness (fever, chills, weight loss), diffuse hand numbness attributed to CTS, clumsiness, urinary urgency or frequency not retention or incontinence. Provocative tests for radiculopathy are mostly unreliable. C7 is most commonly affected followed by C6.

Signs of C5 involvement include pain in the medial scapular border radiating to the elbow, weakness of the deltoid, supraspinatus and infraspinatus, sensory loss in the lateral arm, and loss of the supinator reflex.Signs of C6 involvement include pain in lateral forearm, thumb and index finger, weak biceps, b-r, and wrist extensors, thumb and index finger sensory loss and loss of biceps reflex.

Signs of C7 involvement ae pain in medial scapula, posterior arm, dorsum of forearm, third finger, weak triceps, wrist flexors, finger extesnors, sensory loss in posterior forear and third finger, and loss of triceps reflex.

Signs of C8 involvementare pain in shoulder, ular side of forearm, fifth finger, weak thumb flexors, abductors, and intrinsic hand muscles,and sensory loss of the fifth finger.

Treatment is not proved in large trials. Analgesics including opiates and NSIAA's are first line sometimes with prednisone. Epidural injections result in relief that is longstanding in many patients but complications include spinal cord and brainstem infarction. Hard/soft cervical collar for short term or cervical pillow at night are used. Cervical traction is unproved. Exercise therapy including active AROM, aerobic conditioning with isometric and progressive resistive exercises are usually recommended after initial period.

Indications for surgery include cervical root compression on imaging, concordant pain or dysfunction, persisting pain, or functional motor deficit, or compression of the cord. Anterior decompression with strut reconstruction is common.

Clinical feature and prognostic factors in adults with bacterial meningitis

van de Beek B, de Gans J, Spanjaard L et al. NEJM 2004; 351: 1849-59. Dutch study analysed 696 cases of community acquired acute bacterial meningitis seen 1998-2002. The classic triad of neck stiffness, fever, and change of mental status was seen in only 44 %, but 95 % had two of the four symptoms (the fourth symptom being headache). Mortality was 21 % and much higher with pc meningitis than mc meningitis (30 v. 7 %). Risk factors (negative risk) were advanced age, present otitis or sinusitis, absent rash, low GCS on admission, tachycardia, positive blood culture, elevated sed rate, thrombocytopenia, and low CSF WBC. Worst risk thus was with systemic compromise, low level of consciousness and infection with SC.

In more detail, HA occurred in 83 %, fever in 77 %, change in mental status in 69 % (GCS <14). Rash was present in 26 % and usually indicated mc infection (98 % of time) . 89 % of rashes were petechial. Only 3 % of those with information had papilledema.

Discussion of steroids: The european dexamethasone study showed adjunctive treatment with corticosteroids was beneficial although a posthoc analysis showed it to be more likely due to reduction in systemic than neurologic complications.

HABC Hypomyelination of basal ganglia nad cerebellum

van der Kmaap MS, Linnannkivi T, Paetau A et al. Hypomyelination with atrophy of the basal ganglia and cerebellum: followup and pathology. Neurology 2007; 69: 166-171.

A report of 11 new patients is made. Typically a pediatric population presented with normal or delayed psychomotor development, with increasing extrapyramidal movement disorders, spasticity and ataxia. The putamen was small or absent, the caudate often atrophic with normal thalamus and globus pallidus. The cerebellar granular layer was typically affected. All known patients were sporadic. This is a recently described syndrome (2002) with less than 20 reported cases.

Impulse control and PD Quick hits AAN 2008

1. Patients with PD showed altered decision making under ambiguity but had preserved decision making under risk conditions with explicit rules for gains and loss.
2. Acamprosate was used to treat impulse control disorders in 2 patients with PD in whom discontinuation of dopaminergic drugs did not help. It worked
3. Topiramate was used in 8 Spanish patients to reduce ICD and it appeared to work.
4. The ICD spectrum included pathological gambling, hypersexuality, shopping, computer use and binge craving of sweets, which should be specifically sought in the history taking.

AAN 2010
Hoarding may be a component of the syndrome

Neuroopthalmic findings that reliably differentiate PSP and PD

P05.042 AAN book 2008 Brad Katz et al. Salt Lake City Utah

In addition to standard criteria , the following differentiated the 2 disorders: slowed horizontal saccades, square wave jerks, eyelid opening apraxia, abnormal vertical OKN's, lid retraction stare, blink rate and light sensitivity were all implicated. A cutoff score of 2 or more of the the following three features: greater than 5 swj's, abnormal OKN's downward, and lid retraction stare identified all of 28 patients correctly (including placebos).

Hardwick A, Rucker JC, Cohen ML, et al.  Evolution of oculomotor and clinical findings in autopsy proven Richardson syndrome.  Neurology 73; 2122-2123 2009.

Authors note the SPEED of vertical saccades (more than amplitude) remain the cornerstone for differentiating PSP from other disorders.  Clinical presentation was young, absent falls, complaints of horizontal diplopia due to vergence abnormalities, cognition c/w FTD.  At autopsy atrophy was restricted to the superior colliculi with rare NFTs.

Hemiparkinson-hemiatrophy syndrome

Wijemann S, Jankovic J. Hemiparkinsonism-hemiatrophy syndrome. Neurology 2007; 69: 1585-1594.

Seminal description was made by Klawans in 1981 (Neurology) with hemiatrophy beginning in childhood and hemiParkinsons beginning in early adulthood (before 45). The hemiatrophy may be unnoticed. Symptoms usually begin ipsilateral to the hemiplegia but may spread to the other side. The condition may progress slowly and respond variably to levodopa. This series of 30 patients is the largest to date published. Patients may present initially with dystonia, that is often action induced and may involve the leg or arm only, induced by walking, running, or writing. There was no right or left sided predominance. Patients could present however, with early morning dystonia, tremor, bradykinesia, or gait imbalance. Patients often had scapular winging, raised shoulder , unequal leg length, brisk reflexes and extensor plantars. Occassionally patients had problems in pregnancy or early development especially walking. Scoliosis was common. MRI findings include asymmetric lateral ventricles, volume loss, thalamic or arachnoid cyst. Unilateral changes including calvarial thickening, expansion of the ethmoid, frontal or mastoid sinus, and elevation of the petrous ridge and greater wing of the sphenoid as in the Dyke Davidoff Mason syndrome are reported.

Negative signs and symptoms, that is thsoe infrequently or not seen, include axial signs such as swallowing or speech difficulty or symmetric freezing (although one patient had a relatively unusual sign of unilateral freezing).

The hemiatrophy involved, in order of frequency, hands, feet and face. Some patients first noted difficulty fitting shoes. Its developmental character differentiates it from atrophic conditions such as the Parry Romber syndrome or linear scleroderma. Perinatal injuries are not universal and some cases are traumatic, such as a patient who suffered a gunshot wound to the head at age 6.

Genetic mutations such as the parkin mutation are reported, albeit rarely.

Surgery has been used including VIM DBS, bilateral STN DBS

The authors speculate that patients might have less dopaminergic neurons at birth, perhaps due to a toxin such as lipopolysaccharide, paraquat, or fungicide maneb.

Tegretol and Asians

before giving screen for HLA B1502

FDA warning for rash risk: http://www.fda.gov/cder/drug/InfoSheets/HCP/carbamazepineHCP.htm

tamiflu and delirium

Tamiflu Label Updated with Neuropsychiatric Warning
The FDA and Roche Laboratories have revised the product label for Tamiflu (oseltamivir phosphate) to include a warning on possible neuropsychiatric events. The updated label is based on recommendations from the agency's Pediatric Advisory Committee meeting in November 2007.
Postmarketing reports indicate that some patients with influenza who were receiving Tamiflu had delirium and abnormal behavior leading to injury and even death. Most of the cases occurred in children and in Japan.
Although it's not clear whether Tamiflu caused these events, the label cautions clinicians to monitor their patients for abnormal behavior when taking the drug. Adverse events should be reported through the FDA's MedWatch site.
FDA alert (Free)
Tamiflu prescribing information (Free PDF)
FDA's MedWatch site (Free)

Ictal heart rate differentiates epileptic from nonepileptic seizures

Opherk C, Hirsch LJ. Neurology 2002; 58: 636-8.

Quick and dirty: Documenting an increase in HR during a spell of unresponsiveness usually can differentiate epileptic and psychogenic seizures. Study included 67 epileptic seizure patients and 38 psychogenic seizure patients. Analysis was of quiet staring spells. The positive predictive value was 97 % by using a cutoff of 30 % over baseline.

AAN 2010:  PO5:212  Periictal heart rate changes in patients with localization related epilepsy.  Jeong et al.  33 patients. HR changes were observed in 70 % of seizures, usually tachycardia.  (66% TACHYCARDIA, 4 % BRADYCARDIA) more often in right sided epilepsy than left (77v. 50 %) more in nonlesional than lesional epilepsy (82 v. 45 %)  and much earlier in mesial TLE than extratemporal epilepsy ( -54 v. -6 seconds) which may be useful to predict an epileptic event.

Singing paraplegia: a distinctive manifestation of spinal dural arteriovenous fistula

Khurana VG, Perez-Terzic CM, Peterson RC et al. Neurology 2002; 58: 1279-1281

Case is included because of the extreme difficulty diagnosing spinal dural av fistulas. They may be worse with upright posture, ambulation, pregnancy and menstruation.

The case is a baritone who had a progressive myelopathy with recurrent paraplegia while singing. (He changed from singing while standing to singing while sitting). He had had insidious bilateral leg weakness while bending forward, without pain or bowel or bladder dysfunction. He did have chronic numbness and paresthesias in his feet. He had T2 signal change in mid to low thoracic area, later from T7 to conus with an enlarged cord. A spinal angiogram showed the fistula with an arterialized vein. The fistula was obliterated surgically and the patient became much better, ambulated better and could sing while standing.

The authors discuss that the slowly progressive myelopathy is due to chronic venous hypertension with postnidal venous engorgement and intraparenchymal cord edema and ischemia. Despite the location of the fistula itself, the MRI changes are almost always in the lower cord , attributed to orthostasis and exacerbated with ambulation. In this case, increased venous presure with Vasalva (respiratory exertion during singing) exacerbated venous engorgement and cord edema and ischemia (the pathogenesis involves "marginal" venous drainage).

Common misdiagnoses include disc herniation, canal stenosis, Guilian Barre syndrome, subacute combined degeneration, transverse myelitis, or spinal cord neoplasia. Many misdiagnoses lead to irreversible neurologic changes.

Results of radiotherapy for drooling in ALS

Stalpers LJA, Moser EC. Neurology 2002; 58: 1308.

19 patients with ALS and sialorrhea were treated, all had failed anticholinergic drugs. They got 12 Gy in 2 fractions once a week. That is equivalent to 16 Gy in 8 fractions. 74 % had a complete or partial response. AE's included parotid area pain and mouth dryness. (Netherlands).

Blogger comment question: Can one dare use botox in ALS patients?

Late onset Friedreich ataxia: phenotypic analysis, MRI findings and review of the literature

Bhidayasiri R, Perlman SL, Pulst SM, Geschwind DH. Arch Neurol 2005; 62: 1865-1869.

Definition: age greater than 25, associated with expansion of GAA repeats in the 1st intron of the X25 gene on chromosome 9.

13 patients are described. All had gait and limb ataxia. Many had dysarthria, oss of vibratory sense and abnormal eye movements. More often they had lower limb spasticity, retained reflexes and no sphincter disturbance or cardiomyopathy. Many had vermian cerebellar atrophy. The authors conclude that patients with the above presentation should be tested for GAA expansion in the FA gene.

This contrasts to the Quebec Cooperative Study criteria that defined FA as beginning before age 20 or the Harding criteria that defined FA as having onset before age 25. LOFA overall had more retained reflexes, slower progression, present neuropathy on nerve conduction testing, and less associated conditions (diabetes, scoliosis and cardiomyopathy).

Blast injuries (including neurologic complications)

Depalma RG, Burris DG, Champion HR et al. NEJM 2005; 352: 1335-1342.

1. Blast wave has a shock wave of high pressure followed by a blast wind of air motion. The physics are nonlinear and complex, and damage decreases exponentially with distance from the source. Inddors, reflections and reverberations produce additional unpredictable damage. Enhanced blast explosive devices outdoors can be more damaging. The pressure effects damages organs at air-fluid interfaces, and the wind propels fragments and people causing penetrating or blunt injuries.

2. There are 4 types of blast inuries: primary (effect of pressure), secondary (effect of projectiles), tertiary (effects of wind) and quaternary (burns, asphyxia and exposure to toxic inhalants).

Primary blast injuries-- barotrauma-- at air fluid interfaces are due to interaction of a high frequency stress wave and a lower frequency shear wave. Most important are rupture of the tympanic membranes, pulmonary damage and air emboli (including to brian and spinal cord) rupture of the hollow viscera. The eardrum can rupture with an increase of pressure as small as 5 psi above ATM (about 1/3 atm or 250 mm Hg). Deafness, tinnitus and vertigo results. Pressure gradients of 56-76 psi (3.9-5.2 atm) are needed to damage other organs. Occassionally people have other damage without eardrum damage. Lung injuries include bihilar butterfly pattern on CXR, PTX, hemothorax, pneumomediastinum, and and subcutaneous emphysema. Frothing at mouth (pulmonary edema) with whiteout CXR has a grave prognosis. Body armor protects against projectiles but not against barotrauma including pulmonary barotrauma.

Systemic gas emboli affecting the brain or spinal cord must be diferentiated from head trauma and concussion.

Colonic rupture or occassionally other organ rupture or infarction may be initially difficult to detect and are associated with proximity to blast center. Barotrauma to the eye can cause globe rupture, serous retinitis or hyphema.

Secondary blast injuries-- penetrating fragments are the leading cause of death and injury in attacks, except for major building collapse.

tertiary injuries-- includes crush injuries (buildings), leading to oliguric renal failure; compartment syndromes, characterized by pain out of proportion to the injury. In an earthquake in Japan (1995) mortality increased in patients trapped more than 24 hours due to tertiary injuries.

Quaternary-- includes everything else

Myositis with fever and tick borne illnesses

1. Toxoplasmosis causes myosits and hepatitis but usually not high fevers or DIC
2. Lyme disease from deer tick peaks in spring when nymphal forms are feeding. The bites look like blood blisters and may be unnoticed. It occurs in the upper midwest as well as New England.
3. Deer tick also causes human granulocytic ehrlichosis and babesiosis. The former is caused by the lone star tick which is seen in the southern US and not New England. Babesiosis usually causes anemia, and is worse among patients who are old or immunosuppressed or asplenic.
4. The dog tick or wood tick transmits Rocky Mountain spotted fever and tularemia. RMSF causes a vasculitis with headache and a rash. Tick borne tularemia causes an ulceroglandular disease then an eschar and lymphadenopathy.
5. The ornithodoros tick transmits relapsing fever but again not in New England.

Ehrlichosis has a 7-10 day incubation period, multiorgan involvement, HA, myalgias and malaise, with mortality of 1-10 percent. Patients may have (less than 50 %) n/v/d/cough/stiff neck and mental status changes. They may have pancytopenia,a left shift, lymphocytosis, and elevated transaminases. It DOES NOT RESPOND TO MOST ANTIBIOTICS OTHER THAN DOXYCYCLINE

Combination therapy for neuropathic pain

Gilron I,Bailey JM, et al. Morphone, gabapentin or their combination fo rneuropathic pain. NEJM 2005; 352: 1324-1334 (article) and editorial Raja SN, Haythornthwaite JA. Combination therapy for neuropathic pain-- which drugs, which combination, which patients: NEJM 2005; 352: 1373-5.

In the article, authors study 57 patients with diabetic neuropathy or postherpetic neuralgia, and found that the combination titrated concurrently achieved better analgesia at lower doses of each drug than either one as a single agent.

In clinical management, expert panels suggest that when relief with gabapentin is incomplete, to add a second agent, which may be an opiod.

Postpartum headache

Positional HA described, CT shows an air bubble, headache treated successfully with a blood patch.

Mimic syndromes in sporadic cases of progressive spinal muscular atrophy

Visser J, van den Berg-Vos RM, Franssen H et al. Neurology 2002; 58:1593-1596.
This is a progressive disease of lower motor neurons, aka progressive muscular atrophy, progressive spinal muscular atrophy, and others. Often patients develop UMN signs and qualify for a diagnosis of ALS and these patients are often considered part of the ALS spectrum. The study in the Netherlands was of 89 patients, 17 of whom had other diagnoses in the end. Patients were specifically excluded if they had objective sensory signs, history of diseases that could mimic PMA (spinal radiculopathy, poliomyelitis, diabetic amyotrophy), familyhistoryof SMA, or upper motor neuron signs. 7 patients ultimately met criteria for MMN, 2 with CIDP, 1 limb-gircle dystrophy, 1 inflammatory myopathy, others idiopathic chronic neuropathy, brachial plexopathy, syringomyelia and myopathy. One patient a HNP that recovered, and one had slowly progressive ALS.

Ross syndrome plus: beyond Horner, Holmes-Adie and Harlequin

Shin RK, Galetta SL, Ting TY. Neurology2000; 55: 1841-1846.

Ross syndrome is defined by the triad of tonic pupils, hyporeflexia, and segmental anhidrosis. Holmes-Adie is tonic pupils and areflexia, and harlequin is segmental anhidrosis without ocular changes.

Fatal initial adult-onset presentation of urea cycle defect

Lien J, Nyhan WL, Barshop BA. Arch Neurol 2007; 64:1777-1779.
Ornithine transcarbamylase (OTC) deficiency more commonly occurs in neonates,but can occur in adults. It leads to elevations in ammonia, encephalopathy and coma due to cerebral edema, and death. It is treatable (if diagnosed) with hemodialysis, intravenous arginine, and sodium benzoate/phenylacetate.
In this case report, a 20 yo presented to UCSD with metabolic disease 7 months after her father sudenly became hyperammonemic and died at 52. She had NO other family or personal medical history of prior episodes, and exam was normal. Her father awaoke 8 days after surgery for a throat polyp confused and combatative, developed seizures and had ammonia of 4202. He had cerebral edema and punctate pontine hemorrhages at autopsy.

The daughter later became pregnant with twins, and amniocentesis showed a mutation in both fetuses. She was then admitted given oral citrulline and a low protein diet. The first baby was delivered at 33 weeks vaginally, subsequently intubated, treated with a low protein diet, iv arginine and oral citrulline one he tolerated enteral feedings and did well.

The second baby also had perinatal problems but was treated as above and did well, both discharged at 6 weeks on low protein diets and citrulline and remained healthy.

The differential of the high ammonia in the father included disorders of fatty acid oxidation of organic acidemias. Plasma amino acid levels were normal ( including glutamine, alanine, citrulline, arginine) and urine for organic acids were normal (Orotic acid, uracil). PCR showed a change in codon 208 of exon 6 from GCA to ACA, as happened in amniotic fluid of his grandsons.

These patients are relatively easy to treat once diagnosed, and no longer are the province of pediatric neurologists alone. PEARL-- female heterozygotes are often asymptomatic or minimally symptomatic.

Differential- of headache progressing tohyperammonemic coma can occur with any disorder of the urea cycle. Hyperammonemic citrin deficiency (citrullinemia type II) usually presents in adulthood, sometimes with sometimes without intrahepatic cholestasis and can result in death. Hyperammonemic coma can occur in hyperornithemia, as well. There are over 300 mutations known. Plasma amino acids can show elevated glutamine, alanine or aspartic acid. Citrulline may be low. Organic acids in the urine can show orotic acid or uracil high. Enzyme assay requires liver biopsy but 80 % of diagnoses are made by sequence analysis at this point.

Minocycline in ALS

Gordon PH, Moore DH, Miller RG et al. Efficacy of minocycline in patients with amyotrophic lateral sclerosis: a phase III randomised trial.

412 patients were randomized to placebo or minocycline in doses up to 400 mg/day for 9 months. Primary outcome measure was rate of change in the revised ALS functional rating scale (ALSFRS-R). Patients in the minocycline group declined faster and had a trend to declining FVC faster.

Background hypothesis is that minocycline inhibits cell death for apoptosis. It prolongs mice lives in transgenic models of ALS. Trials are done or planned in Parkinson's disease, Huntington's disease, stroke, dementia, and multiple sclerosis. Authors state the "justification for these trials should be reassessed."

Blogger note: Almost simultaneous, ECTRIMS 2007 reported a disappointing trial of minocycline in MS, and Neurology reported a positive trial regarding the use of minocycline in acute ischemic stroke, the details of which are blogged at the link below.


see also blog about minocycline in stroke:
http://strokenotes.blogspot.com/2008/02/minocycline-treatment-for-acute-stroke.html

Succinic semialdehyde dehydrogenase deficiency (SSADH)

Pearl PL, Gibson KM, Acosta MT, et al. Clinical spectrum of SSADH. Neurology 2003; 1413-1417.

Or, how to have at least a little familiarity with this entity. This is based on a review of 51 patients, ages 1-21 at diagnosis.SSADH is also called 4 hydroxy butyric aciduria.

The presentation during childhood is psychomotor seixures, hypotonia, and nonprogressive ataxia, disproportionate language impairment, behavioral abnormalities including aggressiveness, anxiety, hallucinations, and self injurious behavior. Developmental delay, hypotonia, and mental retardation are the major clinical manifestations. Ataxia, behavior problems seizures and hyporeflexia appear in slightly less than half, and the syndrome is slowly or nonprogressive.

EEG shows generalized and focal epileptiform activity, photosensitivity, background slowing,sleep asynchrony, and was normal in about half. MRI showed T2 hyperintensities in the globus pallidus bilaterally and symmetrically.

The treatment is obscure-- the authors discuss the rationale of vigabatrin (nonapproved) in the GHB pathway , notes the Depakote is contraindicated as it inhibits any remaining SSADH. Naloxone reverses GHB-mediated inhibitory effect on striatal dopamine release.

Biochem--SSADH + GABA transaminase convert GABA to succinic acid. In SSADH, GABA instead converts to 4-hydroxybutyrate. GHB accunulates in urine, serum, and CSF of patients. The gene maps to chromosome 6p22. Standard organic acid screens miss the increased excretion of 4-oh- butyric acid. Only a small peak obscured in a large urea peak may appear. It is necessary to add a selective ion monitoring mass spectrometry screen for specific compounds to make the diagnosis.

GHB is an endogenous metabolite and neurotransmitter. It is used to manage cataplexy and opiate and alcohol withdrawl, as a recreational drug of abuse, and to subdue victims for sexual assault. Please see related posts on GHB and toner cartridge abuse.
http://www.blogger.com/post-edit.g?blogID=30837446&postID=1017610194363222736

http://www.blogger.com/post-edit.g?blogID=30837446&postID=1017610194363222736

Rabies transmission through solid organ transplantation

Burton EC, Burns, DK, Opatowsky MJ, El-Fekt WH, et al. Raies encephalomyelitis. Clinical, neuroradiological, and pathologic findings in 4 transplant recipients. Arch Neurol. 2005; 62: 873-882.

Rabies has been transmitted through animal bites, most commonly bats, also through corneal transplants. 4 individuals received organs from a single donor with unsuspected rabies who had suspected cocaine induced agitation. All recipients were readmitted within a month of receiving their organs with symptoms that rapidly progressed to coma and death. Theyincluded sleep deprivation, tremors, decreased appetite, abdominal and back pain, itching (one underwent appendectomy for abdom pain), delirium, myoclonus, and eventually death.

LP done on 3 patients, all had normal glucose, 2 had high protein (69,229), all had increased cells (7-32), all had negative viral cultures.

MRI's were bilaterally abnormal in PVWM, leptomeninges, medial temporal lobes, inferior frontal lobes, subinsular cortex, precentral gyus, basal ganglia, thalami, midbrain, hippocampi , cerebral peduncles and cerebellum. Initial CT's were all normal.

EEG's showed moderate to severe slowing, one patient ultimately had seizures. Diagnosis was made at post mortem.

The cardinal signs of classic rabies encephalitic form are fluctuating consciousness, phobic spasms, and autonomic dysfunction. Bat rabies patients canhave local pain at bite site (burbing, numbness, itching, but might be unknown). Symptoms reported include anisocoria, bilateral ptosis, diplopia, nystagmus, pinpoint pupils, intermittent facial palsy, tremor, and rarely seizures (especially in bat rabies). Also, patients may experience hemiparesis, hemisensory loss, assymmetric reflexes or cranial neuropathies.

Drugs causing myoclonus

Neurololgy 2002; 58:984-985

Antidepressants
MAOI
TCA's
Lithium
Antibiotics
penicillin
ticarcillin
carbenicillin
cephalosporins
Anesthestics
etomidate
enflurane
chloralose
Anticonvulsants
valproic acid
carbamazepine
clozapine
vigabatrin
Calcium channel blockers
verapamil
nifedipine
opiate derivatives
meperidine
methadone
morphine
oxycodone
Other drugs
bismuth
chlorambucil
Overdoses or poisonings
antihistamine overdose
methyl bromide fumes
organic mercury poisoning
gasoline sniffing
dichloroethane ingestion
strychnine poisoning

Paroxysmal extreme pain disorder (formerly familial rectal pain syndrome)

Fertleman CR, Ferrie CD, Aicardi J. Neurology 2007; 69:586-595.

A large family describes episodes in affected individuals of excruciating rectal pain, flushing of the buttocks and legs, ocular pain, flushing of the eyelids, and periorbital skin, and submaxillary pain. Tonic atacks with bradycardia in infancy and apnea and cardiac asystole with these tonic nonepileptic seizures may be part of the syndrome. The onset may even be in utero. Newborns may be stiff and red. The precipitant for the first attack is usually defecation. Other triggers might include bathing, sudden loud noises, feeding and perineal toilet, cold , wind, eating and emotion. Painful attacks can be divided into rectal, ocular and jaw. However, pain is not restricted to these sites. Flushing is a constant feature and accompanies pain in younger individuals. The pain starts as an itch like pain then burning lancinate, stabbing, and becomes unbearable, the worst pain imaginable. Flushes may be geographic but not always. "Harlequin" color changes are common but not universal and may affect half the face. Other symptoms may include hypersalivation with jaw attacks, watering of eyes, weakness of the affected foot for 24 hours, episodic vomiting, and prolonged recovery from inhalational anesthetics. Tonic attacks are associated with harlequin color changes, can last up to a minute, and leads to several minutes of nonresponsiveness. Symptoms between attacks include constipation (due to fear of precipitating an attack).

Treatment with carbamazepine has been shown to be at least partly effective, completely so in a few patients. High doses are used. Opiates are not effective, and amitryptilene and clonidine are not effective. Inhaled nitrous oxide (Entonex) is used for some of the most severe attacks. Tests are always normal, except tachycardia with attacks. EEG during attack shows slow--flat -slow pattern. The channelopathy is a mutant sodium 1.7 channel .

Differentiate from hyperekplexia in which infants are high toned with increased reflexes. Hyperekplexia is associated with a glycine channel disorder. Children do not respond to pacers with aystole suggesting they are of respiratory not cardiac origin. It si not clear if tonic seizures with asystole pose a threat or not (anoxic seizures are benign, hyperecplectic can be fatal). Primary erythromalgia is caused by mutations in sodium channel gene SCN9A with severe pain and flushing, but occur in the feet and are triggered by warm temperature and exercise. It usually occurs in adult life and fails to respond to CBZ whereas mexilitene is helpful. The disease is lifelong but attacks lessen over time in adulthood.

Evaluating dizzy patients-- historical pearls

Presyncope-- brief light headedness when standing with drop in BP
Benign positional vertigo-- lasts second, triggered with head movement especially in AM when getting out of bed or in pm when getting in . However, a few cases lack classical h/s and present with postural dizziness/falls
Vertiginous migraines-- last 10-30 minutes, are insensitive to position, may be followed by a HA
Meniere's related vertigo may last hours, be accompanied by tinnitus and hearing loss, and is not triggered by motion Vestibular neuritis may have a sudden onset and last days . Patients may describe a "floating sensation"
TIA's last a few minutes and are accompanied by other "brainstem" signs
Orthostatic intolerance-- light headed, dizzy, impulse of falling
Basilar occlusion-- rotational vertigo, nonvertiginous dizziness
psychiatric-- panic disorder-- dizzy/woozy, sudden veers
Hypoglycemia-- light headed, unsteady.

Types of headaches

Migraine types-
1. Classic
2. Common
3. Complicated
4. Retinal
5. Opthalmoplegic
6. Benign mydriasis, episodic as a sign of migraine
7. Basilar (Bickerstaff) migraine
8. Hemiplegic
9. Vertiginous
10. Acephalgic

Non migraine headache
11. Tension
12. ebound
13. Cluster
14. Paroxysmal hemicrania (differentiate from cluster partly by female predominance, shorter duration and response to indomethacin)
15. Sunct syndrome-- unresponsive to indomethacin and SUNA syndrome
16.Ice pick headache
17. Ptussive headache (consider relation to Chiari malformation or rarely subdural hematoma)
18. Thunderclap headache
19. Greater occipital neuralgai
20. Hypnic headache
21. Carotid dissection
22. Temporal arteritis
23. Post-traumatic headache
24. Glossopharyngeal neuralgia
25. Intracranial hypertension (with or without pappilledema)

Headaches related to eye disease
26. Corneal erosion/disease
27. Intraocular disease-- include acute angle glaucoma, scleritis, iritis, uveitis.
28. Optic neuritis
29. Eye strain

Differential diagnosis of ON

1. Anterior ischemic optic neuropathy (AION) often lacks the pain seen in ON
2. Painless visual loss without improvement over several weeks AION
3. Leber's hereditary optic neuropathy (LHON) occurs inyoung men with a mitochondrial disease; the presentation is unilateral unremitting progressive visual loss to bilateral visual loss over days to months with disc edema, peripappillary telangiectasias, and permanent visual loss.
4. Absent venous pulsations-- enlarged blind spot-- consider increased ICP
5. Orbital mass constricting the optic nerve may cause disc edema, proptosis, and EOM restriction unilaterally
6. Diabetic papillopathy in young diabetics often remits
7. Other inflammatory diseases: HIV, syphilis, TB, cryptococcus, toxoplasma, varicella, histoplasmosis, CMV, and h. zoster all can cause ON.
8. Macular star suggests toxoplasmosis.
9. Optic spinal "Asian" MS may be a form of NMO.

Optic neuritis, symptoms and signs

(review in the Neurologist 2000; 6:205-13) author Jane Chan MD
Symptoms

1. In acute ON more than 90 % have loss of central vision. Occasionally patients get loss of peripheral vision to one side or superiorly or inferiorly.
2. Mild orbital pain above or behind the eye, preceding or concurrently with the visual loss, aggravated by upwards movement of the eye, and last up to several weeks. This may be due to triggering of trigeminal stimulation of the optic nerve sheath.
3. Less conmon symptoms are photophobia, dullness or loss of colors, perceptions of phosphenes (flashing lights with noise or eye movements) or decreased depth perception.

Signs
1. Visual loss worsens over hours, days or minutes and peaks within days to a week. Maximal return occurs within 3-6 months and does not correlate to initial visual loss.
2. Patterns of visual field loss was varied as central scotoma resolves to a small dim central or a paracentral deficit. Patterns include an arcuate scotoma, altitudinal scotoma (superior or inferior),peripheral constriction, central or cecocentral scotoma, bitemporal or hemianopic deficit. Patterns can vary day to day or hour to hour.
3. Color and contrast visionare reduced. The color defect is usually more severe than the acuity loss. The Farnsworth-Munsell 100 hue test is highly sensitive and specific. The short version with caps 22-42 has similar sensitivity for monitoring after ON. More blue yellow defects occur acutely, more red green defects occur after 6 months. Patients also have a decreased sensation of brightness.
4. RAPD is almost always present in acute ON; absence suggests optic neuropathy or other etiology.
5. Half of the patients in the ONTT had abnormal fellow eyes (contrateral) and many of these thought their vision contralaterally was normal.
6. PEARL-- RARELY an RAPD occurs in a retrochiasmal lesion due to pupillary fibers travelling together in optic tract

RED FLAGS or atypical features of optic neuritis
1. age greater than 50
2. Optic pallor at presentation
3. no pain
4. pain or vision loss that continues over weeks
5. poor visual recovery
6. associated systemic signs and symptoms

Tests for myasthenia gravis: Pearls

1. Tensilon test should be unequivocal and not subjective. In one study all patients who had a positive test responded in the first 7 mg.

2. False positive tensilon tests occurred in LEMS< GBS, compressive cranial neuropathies and brain stem lesions (Seminars of Neurology 2003, author Pascuzzi).

3. Muscarinic effects (tearing, sweating,cramping, salivating and nausea) are common. Relative contraindications are cardiac arrythmias and asthma. Cardiac monitoring may not be universally required.

4. A neostigmine methylsulfate injection can be used in children with a longer onset and offset (latter is 30 minutes) but may be harder to interpret.

5. The ice pack test of placing the ice pack on for 2-5 minutes has reported high sensitivity and specificity but may be hard to tolerate for patients (Golnick AC et al. Opthalmology 1999 186:1282-6). The mean improvement with this test is 4.5 mm.

6. The rest test (close eyes for 3 minutes) results in a mean improvement of 2 mm of ptosis.

7. The sleep test (30 minutes) shows improvement in all Tensilon positive patients plus two others (out of 42 tested).

8. Lab tests of binding Ach receptors is positive in 50 % of OM patients (v. 90 % of MG patients overall); blocking antibodies add only another 1 percent sensitivity, and modulating antibodies actually do improve sensitivity slightly but also have more false positives. see Howard FJ et al. NY Acad Sci 1987; 505: 526-538).

9. False positive conditions with ACH receptor antibodies (again from Howard et al.) are: AI hepatitis, SLE, ALS, inflammatory neuropathies, LEMS, thyroid opthalmopathy, 1 degree relatives of MG patients, thymoma, RA, and patients taking penicillamine.

10. Striated muscle ab's as a marker for thymoma: they predict thymoma in patients with MG under 40 (80%) and thymoma in nonmyasthenics (positive in 25 % of those). False positives are seen in RA treated with penicillamine, LEMS, Bone marrow graft recipients, GVHD, and paraneoplastic disease (see Lennon, Neurol suppl 5, 1997 S23-27).

11. De Graefe's test 12. Mary Walker phenomenon-- inflation of cuff above normal systolic pressure causes fatigue. Deflation of the cuff causes exacerbation of MG in rest of the body

13. Fatigue-ability is the hallmark of MG. Test for with sustained upgaze test 30-60 sec (especially check medial rectus muscle> superior and lateral recti); sustained abduction of the arms (120 s); sustained elevation of the leg while lying supine (90 sec); repeated rising from a chair without using arms, up to 20 times, look for bfm's; counting aloud to 50.

14. The rare patient that presents with isolated respiratory involvement may have orthopnea, ie SOB while lying down.

15. Enhanced ptosis of contralateral side may occur with manual elevation of one ptotic lid

16. Unilateral frontal hypercontraction is a sign of weak lids.

17. Specific muscles to assess in suspected MG include eom's, oropharyngeal, facial, respiratory, axial and limb

18 Pseudo INO occurs when adducting eye does not adduct and abducting eye has nystagmus

19. Cover - uncover test can reveal weakness if done repeatedly.

20. Beware of holding target to fixate too close, will reveal a convergence abnormality rather than a true EOM abnormality.

21. Look for snarl with attempt to smile, inability to pucker to kiss

22. Pattern of weak jaw closure and strong jaw opening is expected in MG. Test temporalis/pterygoid separately. Weak jaw opening with pterygoid weakness is rarely found in MG.

23.  Fatigue of swallowing does occur in MG

24.  Slurp test touted in May, 2010 Neurology podcast for children with MG that parents can do to test for weakness.   fill 4 oz cup with water with a straw and have child slurp after finishing the drink.  Time it, use patient as own control.  

Signs and symptoms of ocular myasthenia

1. Unilateral or bilateral ptosis, usually variable through the day, with diplopia
2. Chief complaint may be blurred vision if lid covers pupil and ptosis is not recognized.
3. Hyper-retraction of the less affected lid can cause a complaint of ocular irritation due to exposure.Hyperretraction is a compensatory mechanism with increased neuronal firing in less affected eye.
4. Dizziness, gait instability, blurring of "visual confusion" that improves with closing one eye
5. SPECIFIC SIGN OF MG: WHEN PTOTIC LID IS MANUALLY (passively) ELEVATED, THE CONTRALATERAL LID DROOPS
6. Cogan lid twitch sign: The patient looks down for 15 seconds, then rapidly up at the examiner's finger. The ptotic eyelid overshoots and is transiently higher than the contralateral lid then drops to its normal position. Its due to transient strengthening of the lid after resting the levator muscle.
7. Any pattern of EOM weakness
8. Dissociated gaze evoked nystagmus contralateral to the paretic eye.This is adaptive and due to increased pulses of innervation.
9. Orbicularis oculi weakness with ptosis is a strong suggestor of MG.
10. Peekaboo sign with gradual appearance of lagopthalmos after forceful lid closure of over a minute with fatigue and incomplete lid closure showing sclera, hence the name, is also seen in facial nerve disorders
11. Pupils are always normal, unlike botulism and IIIn palsy.
12. The "other" Babinski sign (aka "brow lift sign)-- "when orbicularis oculi contracts and the eye closes, the internal part of the frontalis contracts at the same time and the eyebrow raises during eye occlusion." This sign is helpfulin differentiating MG from blepharospasm.

Differential diagnosis of ocular myasthenia

1.Any IV,VI, and partial IIInn palsies
2. Graves opthalmopathy (however, should not see ptosis, and may see lid retraction)
3. CPEO Chronic progressive external opthalmoplegia(get symmetric ptosis and EOM weakness, but unlike myasthenia, SACCADES ARE SLOW in CPEO
4. Oculopharyngeal dystrophy-- chronic, slowly progressive, family history present, bulbar mm are involved.
5. Glycogenosis type II -- ptosis is presenting feature often (Neurology 69 : 116 2007) with skeletal muscle weakness later. Muscle biopsy may be needed to show increased glycogen content and acid maltase deficiency,
6. Autoimmune encephalitis with diplopia: http://dementianotes.blogspot.com/2008/06/vgkc-autoantibodies-mimicking-cjd.html

Seven agents approved for antimigraine prophylaxis

(list is in Lancet Neurology Dec 2007 editorial, suggests this applies to UK, in case some of the drugs sound unfamiliar). The seven are: methysergide, propanolol, timolol, pizotifen, flunarizine, valproate, and topiramate.

Corticosteroids for bacterial meningitis

editorial Greenwood BM. NEJM 2007; 357:2507-08 (editorial) and (same issue)

Mai NTH et al. Dexamethasone in Vietnamese adolescents and adults with bacterial meningitis pp. 2431-2440

and

Scarborough M et al. Corticosteroids for bacterial meningitis in adults in subSaharan Africa pp. 2441-2450.

The prologue is that meta-analysis in industrialized countries showed that dexamethasone given to children with Hemophilus B type b meningitis before antibiotics reduces sequelae, especially hearing loss (McIntyre PB et al. Jama 1997; 278:925-931. Studies in adults in ind. countries also show a benefit (NEJM 2002; Lancet Inf Dis 2004). A trial of 598 children in Malawi, about one third of whom were infected with the HIV virus, showed "convincing evidence of lack of benefit." Most African pediatricians have accepted the result (Lancet 2002). The study above (Scarborough et al.) of adults age greater than 16 with acute bacterial meningitis given dexamethasone 16 mg bid for four days with ceftriaxone showed no benefit of dexamethasone on any endpoint. In contrast, the study by Mai et al. in Vietnam of 435 persons odler than 14 with .4 mg/kg dexamethasone for 4 days of placebo before ceftriaxone, showed benefits in some analyses on death, hearing loss in treated group (if TB patients are excluded). Notable was the strikingly higher mortality in Africa v. Vietnam (54 v. 11%) possibly due to HIV infection, or a different infection (Str pn in Malawi S. suis in Vietnam). A South American study showed no benefit of dexamethasone, but benefit of glycerol (Clin Infect Dis 2007, author Peltola et al.). Editorial concludes the focus should be on vaccines although dexamethasone might be used in the developed world.

Serotonin syndrome and its differential diagnosis and treatment

Boyer EW, Shannon M. Current Concepts. The Serotonin Syndrome. NEJM 2005; 352:1111-20.

General notes
1. The serotonin syndrome (SS) is not an idiopathic drug reaction but a predictable consequence of excess serotonergic drug stimulation of the CNS and peipheral receptors.

2. It has a spectrum of findings ranging from barely perceptible to lethal.

The classical triad is mental status changes, autonomic hyperactivity and neuromuscular abnormalities. Symptoms can include tremor, diarrhea, delirium, rigidity, shivering, mydriasis, tachycardia, hypertension, and hyperthermia. Inadvertent increase in the dose of a causative drug can provoke a dramatic deterioration.

Drugs and drug combinations include MAOI's, TCA's, SSRI's, opiates, OTC cough suppressants, antibiotics, weight reduction drugs, antiemetics, antimigraine drugs, drugs of abuse, herbal products, drugs that inhibit CYP2D6 and CYP3A4 systems, PAST use of fluoxetine (within 6 weeks), or illegal drug ecstasy. Most cases occur within minutes to hours after initiating a new medicine or increasing a dose. It does not resolve if offending drugs are still given.

Clinical notes: lower extremity hyprereflexia and clonus is much worse than the upper extremity. Horizontal ocular clonus  and opsolclonus may occur. Mutism is not infrequent.  Startle is increased, and repetitive head rotaton may occur. Patients may degenerate into frank shock. Diagnosis: Clonus (inducible, spontaneous or ocular) is the most important finding. The differential includes anticholinergic poisoning, malignant hyperthermia, and NMS which all are differentiated on clinical/historical grounds.

Anticholinergic patients have normal reflexes and "toxidrome" of mydriasis, agitated delirium, dry oral mucosa, hot dry skin, urine retention, absent bowel sounds (always present in SS). Malignant hyperthermia has increasing end tidal CO2 levels, ypertonicity, hyperthermia, and metabolic acidosis, within minutes of exposure to inhalational anesthesia. Skin exam shows mottling, cyanosis juxtaposed to bright red flushing. The skeletal muscles are rigid, and there is areflexia. NMS is an idiopathic reaction to DA agonists with slow onset, bradykinesia, lead pipe rigiditym hyperthermia, fluctuating consciousness and autonomic instability that evolves over hours to days (whereas SS has rapid onset and hyperkinesia).

Management involves removing offending drug, supportive care, control of ANS instability, and occassionally benzodiazepines. Moderately ill patients should aggressively correct CV and respiratory problems and receive 5H2a antagonists. Severely hyperthermic patients (41) should also be sedated, paralyzed and intubated. Benzodiazepines may be life saving. Physical restraints are not advised. The antidote is usually cyproheptadine, giving 12-32 mg over a 24 hour period (initial dose of 12 mg then 2 mg q 2 hours prn, given po, crushed in a Dobhoff). I-m thorazine can be used. Hypertension and tachycardia can be treated with short acting drugs such as esmolol and nitroprusside. Hyperthermia should be treated with nondepolarizing drugs such as vecuronium, NOT succinylcholine. Antipyretics are not indicated since fever is due to muscle activity and the hypothalamic set point is working OK. Propanolol is not indicated as it can cause hypotension and shock, and abolish reflex tachycardia. BCT and dantrolene are not useful (unlike NMS and malignant hyperthermia).

Cyproheptadine can be sedating but that is OK. Chlorpromazine can cause hypotension which is irrelevant.

Therapy for nerve agent poisoning

Newmark, J. Therapy for nerve agent poisoning. Arch Neurol 2004; 61:649-652

Nerve agents include tabun (GA), sarin (GB), soman (GD), cyclosarin (GF) and VX. All evaporate and are gone within 24 hours, except VX which is oily and the only one which is persistent. VX is the most lethal substance known to man. The drugs were weaponized in Nazi Germany, used by Iraq against Iran in the Iraq-Iran war, and used in 2 subway attacks in Japan in 1994-5.

Clinical scenario-- in a shopping mall, you hear a "pop" and see smoke, your vision dims and nose runs severely. People may collapse, breathing heavily or seizing, with constricted pupils.

The mechanism is similar to organophosphate pesticides, although they are much less fat soluble and therefore more toxic. Theyinhibit AchE, acetylcholinesterase, producing a cholinergic crisis. Most exposures occur through the vapor route and act within seconds to minutes. The initial symptoms are miosis and rhinorhhea and salivation. Later, brochorrhea and bronchospasm occur. They are absorbed at the alveoli, and although they are not important clinically, the gold standard of diagnosis is RBC AChE. Circulating toxin first affects the GIT causing cramping, pain, nausea and defecation. It will affect the heart variably with unpredictable effects on BP and HR. They cause massive overstimulation of peripheral neuromuscular synapses witha progression from fasciculation to twitching that may be misinterpreted as a seizure. When ATP is depleted (a late finding) the patient will eventually have flaccid paralysis. Rapid CND cholinergic stimulation will cause LOC, seizures, inhibition of medullary respiratory center with central apnea. Death is due to respiratory failure (combined) due to bronchospasm, bronchorhhea, inadequate function of respiratorymuscles, and central apnea.

Liquid exposure has a longer slower onset and offset than vapor. Skin decontamination may not suffice if not done immediately, as nerve agent may be trapped subcutaneously and continue to penetrate.

Patients recovered frommild poisoning have a neurobehavioral syndrome including HA, personalitychange, depression, and higher order problemswith memory and reading. It may resemblePTSD or postanoxic encephalopathy. Chronic effects are few, with one report of a PN and a few of vestibular problems.

THERAPY:
Ventilatory support can be lifesaving even for someone in full arrest, if an antidote is given. Treatment has not changed since 1945 and includes an anticholinergic drug to counteract crisis, an oxime to reactivate inhibited AChE, and an AED to prevent seizures. In the field,atropine is used with i-m autoinjectorswith an initial therapy of 2,4,or 6 mg with retreatment every 5-10 minutes as needed. 0.5 or 1.0 mg ampules are available for children. In the hospital it may be given intravenously. Atropine binds to muscarinicreceptorsbut not nicotinic receptors, so twitching and dyscoordination will continue. The respiratory problems are life threatening and atropine saves lives,per the Iranian experience.

The fielded oxime is 2-pralidoximm chloride (2 PAM). The i-m dose is 600 mg per autoinjector. The upper limit is 2000 mg/hr due to the risk of sudden elevation of blood pressure. Oximes reactivate catalytic cholinesterase and simultaenously split nerve agent or organophosphate insectisides into harmless, rapidly metabolized fragments. After nerve agent binds AChE , the resultant complex spontaneously loses a side chain ("aging") rendering the remaining enzyme-inhibitor complex unable to be reactivated by oxime. Most nerve agents age slowly and the reaction can be ignores (sarin over hours, VX over days to weeks) but soman over two minutes. Once the complex has aged, the oximes are useless although not harmful to the patient.

The MARK 1 set (Meridian Medical Technologies, Columbia, MS) has a 2 mg atropine and 600 mg 2-PAM autoinjectors and is already approved by the FDA for the general use.

Standard AED's (antiepileptic drugs) are not useful for seizures due to nerve agents. Only benzodiazepines are effective. The military uses diazepam 10mg autoinjectors. Midazolam is the most effective, given i-v, in terms of speed of actions, low dose required, and broad spectrum. Epilepsy does not develop and chonic AED's are not advised.

The fourth drug available is pyridostigmine bromide, which may be useful if soldiers are concerned about a rapidly aging poison (soman) . Pyridostigmine will sequester a percentage of the patients excess AChE and render it unavailable to be irreversibly inhibited by a a nerve agent. Therefore a lethal dose becomes survivable with antidotes.

Care must be provided inthe field, not in the hospital (too late). Additional information is available at the chemical casualty division website at http://ccc.apgea.army.mil or the Army Medical Research Institute of Chemical Defense at (410) 436-3276.

Multiple auras: clinical significanceand pathophysiology

Widdiss-Walsh P, Kotagel P et al. Multiple auras: clinical significance and pathophysiology. Neurology 2007; 69:755-761.

Ninety percent of those with two aura types and 100 % of those with three aura types have right hemisphere localization of their seizures. Some examples were rising epigastric sensation with a simultaneous unpleasant odor or visual field distortion. Multiple auras previously are considered commoner in in patients "alien tissue" (v. mesial temporal sclerosis).

Miscellaneous drug facts most people do not know

 Antiepileptic drug random facts
1. Phenytoin (more misc. on than we already new)- a.   increases HDL levels.
    b. Formula to adjust PTN dose.  In zero order kinetics, a fixed AMOUNT not percentage of phenytoin is metabolized.  Vd= .7 L/kg     Loading dose = (Vd) x (desired change in concentration)  so eg. raise the level from 5 to 18 in a 100 kg man would mean Vd=70L, loading dose = 70 x 13= 910 mg.  Phenytoin is saturably absorbed in duodenum and affected by food and by antacids

2.  Cerebyx has the same Tmax as Dilantin due to time required to cleave the "fos" of fos phenytoin. Cerebyx also has some cardiac toxicity despite the absent phenylene glycol adjuvant.  Infusion can be faster than Dilantin but not more than 150 mg/min. It prevents the purple glove but not time to treat SE.

3. PTN, CBZ and PB block efficacy of some chemotherapeutic agents (see post)http://neurologyminutiae.blogspot.com/2007/11/drug-interactionsenzyme-inducers-and.html

4. Depakote
a.  may be useful in brain tumor treatment irrespective of AED effect (see post) http://neurologyminutiae.blogspot.com/2007/07/valproic-acid-and-brain-tumors.html
b.  Depakote is highly bound but not to albumen; and free levels are difficult to measure.  Its level rises in cirrhosis.  Its path is 80 % direct glucuronidation, 17 % is in same oxidative path as free fatty acids and enters the carnitine shuffle, leading to 4, en VPA.  Many ICU patients are carnitine deficient which shunts VPA to toxic metabolism so give these patients carnitine 25 mg/kg png over six hours leads to less NH4+.

5. Vimpat can cause angioedema

DRUGS FOR DEMENTIA

1. Rivastigmine patches can be left on for more than 24 hours as they have a 24 hour half life (in effect, patients are throwing away active drug). Wearing multiple patches, duly labelled, is one way to dispense a higher dose, usually with limited adverse effects

 2. Memantine has histamine blocking properties and its use may limit GI adverse events of individuals taking rivastigmine or other drugs.

3. Cholinesterase inhibitors inhibit metabolism of suxamethonium, prolonging neuromuscular blockade


OTHER
1. Prazosin is highly effective for post-traumatic stress disorder
2. Levodopa-carbidopa and gabapentin are two rare drugs that are gastric absorbed and in fact compete with each other. Better to stop the gabapentin in Parkinson patients.3. Protease inhibitors potentiate toxicity of GHB, so HIV patients attending circuit parties are at extra high risk of coma and death.
4. Drug rash to Sinemet is due to yellow dye not levodopa carbidopa (see post) http://neurologyminutiae.blogspot.com/2007/04/rash-to-yellow-dye-in-levodopa.html
 5. Natalizumab also blocks trafficking of B cells into CNS
 6. . Atorvastatin, even brief exposure, causes a marked decrease in blood Co Q 10 concentration (shares the synthetic pathway of cholesterol). Primary CoQ10 deficiency causes mitochondrial encephalomyopathy with recurrent myoglobinuria; this may pertain to AE's of atorvastatin. Also, CoQ10 is an excellent free radical scavenger and the effects on degenerative disease are not known. Rundek et al,. Arch Neurol 2004; 61: 889-892.

A 16 year old girl with progressive weakness of the let leg

Hahn AF, Mauermann ML, Dyck PJB, Keegan BM/ CPC. Neurology2007;69:84-90. Insidious onset of left LE weakness started at age 13, progressing to complete footdrop. She had normal sensation and reflexes. She had gobs of negative tests. Motor exam showed mild weakness in posterior tibialis and hamstring, severe weakness in the tibialis anterior, to extensors and peroneii, and normal gastrocnemius and toe flexors. She had mild pes cavus. EMG showed normal left tibial nerve conductions, left peroneal motor and surals were absent or severely abnormal. Needle testing showed marked denervation distal to the short head of the biceps. QST's were normal. MRI showed mild increase int he size and signal intensity of the left peroneal nerve in the peroneal division only. Anatomic localization implicated the common peroneal nerve or divisional sciatic nerve. Discussant notes that the tibial and peroneal divisions of the sciatic nerve are segregated as the sciatic nerve passes from the sciatic notch, so a sciatic lesion can mimic a peroneal neuropathy. In such cases needle EMG of the short head of the biceps is crucial. MRI neuronography showed enlarged peroneal nerve ipsilaterally. The diagnosis on biopsy of the nerve was intraneural perineuroma (aka localized hypertrophic mononeuropathy). It presents as a painless motor mononeuropathy in younger patients in a variety of nerves (posterior interosseous, radial ulnar). MRI differentiates from fibrolipomatous hamartoma, but not intraneural ganglion cysts. Intraoperatively, internal neurolysis can suggest the diagnosis also. Unlike true onion bulbs, which are S100 positive, these are S100 negative and EMA positive.

SSPE

Cole AJ, Henson JW, Roehrl MHA et al. Case 24-1007: A 20 year old pregnant woman with altered mental status. NEJM 2007; 357: 589-600.

Case showed a young pregnant woman with clinical presentation of aseptic meningitis: confusion, lymphocytic pleocytosis in CSF, FIRDA on EEG, ,MRI showing dysfunction in a non hSVE pattern affecting internal capsule and cerebellar outflow tract, gads of negative tests. MRI affected left temporal lobe and pons. The patient had chorea which brought up Strep infection and Syndenham's chorea but ASO was only minimally positive and ACL's were negative. There was marked increase in CSF IgG levels, IgG index and oligoclonal bands. According to Dr. Cole, that narrowed it to syphilis, chronic rubella encephalitis, and SSPE.

Measles causes 3 different CNS diseases: postinfectious encephalomyelitis, subacute measles encephalitis, and SSPE. SSPE occurs 7-10 years after infection with behavioral changes, headache, adventitious movements, and sometimes seizures. Myoclonic jerks and PLEDs on EEG may occur. It may occur from childhood until fifth decade of life. It persists in places where measles vaccination remains uncommon. It is more common if measles occurred at age < 2 years, and may be more common in pregnancy. The diagnostic test is measles specific CSF IgG antibody index compared to serum. Iit maybe compared to a control infection such as mumps. This patients was treated with interferon and pranobex for eight weeks, delivered a healthy baby and then expired. SSPE is considered almost always a progressive disease. This patient may have shown signs in a prior pregnancy of a movement disorder.

Drug interactions,enzyme inducers and anticancer

PTN, CBZ and PB induce cytochome P450 and reduces bioavailability of many chemotherapeutic drugs and warfarin. The former include camptothecins (topotecan and irinotecan) and taxanes (paclitaxol).

Mayo Clin Prcds combination of risperidol and gingko caused priaprism