Wednesday, 21 December 2016

Dermatomyositis

Case

A 72 year-old female presented in June 2015 with rash on her hands, face and around her nostrils. She was referred to dermatologist, skin biopsy was performed and showed lichen planus, which was subsequently treated with topical steroids and emollients.

5 months later rash recurred, spreading to the arms and torso. She developed progressive myalgia affecting the neck and proximal limb muscles in combination with progressive swallowing difficulty. Mobility deteriorated such that she started to fall in the community and was unable to perform activities of daily living independently.

After dermatological review polymyalgia rheumatic was suspected for which she was started on 20 mg prednisolone. Despite this, two months later she was unable to stand or sit without assistance. Further deterioration in swallow resulted in presentation to Whipps Cross Hospital and subsequent transfer to Royal London Hospital.

Interview revealed no significant past medical history except for idiopathic thrombocytopaenia and longstanding osteoarthritis. She was on no regular medication and had no history of alcohol use or smoking.


On examination she was short of breath (FVC<0.9) and failed both bedside and formal swallow assessments. There was a heliotrope rash and Gottron’s papules as well as erythematous rash on left elbow, torso and behind both ears. There were dry mucous membranes (eyes and mouth). Weakness was pronounced in the proximal muscle groups with distal sparing. She was areflexic, sensation was intact.

Investigations
Blood results showed normal ESR and CRP with increased CK of 900, ANA 1/160 and ENA negative.
MRI head and whole spine showed increased signal within the neck and paraspinal muscles.
Nerve conduction studies showed incidental mild left carpal tunnel syndrome, whilst needle EMG sampling revealed no spontaneous activity in any of the muscles sampled. However, voluntary activated motor units were markedly polypahsic and short in duration with evidence of early recruitment. 
Muscle MRI showed increased signal in relation to the musculature of the pelvic girdle  and within the thigh musculature bilaterally, which would support the diagnosis of myositis.
Muscle biopsy showed widespread upregulation of MHC Class I, fibre necrosis with prominent macrophagic (and milder lymphocytic) infiltration as well as fibre regeneration.

Diagnosis
Inflammatory myopathy with dermatological involvement (Dermatomyositis)

Next steps
The priority was to excluding underlying malignancy.
CXR, CT CAP and Mammogram were performed.
CT CAP showed early bronchiectatic changes in the left lung base but no malignancy. Mammogram showed a dense, nodular background pattern with scattered benign calcifications.

PET revealed mildly increased uptake in the muscles and basal pleural thickening.

An extended ENA panel including HMGCR antibodies were negative. Anti-TIF1 gamma antibody was positive.


Treatment:
The focus of acute treatment was to control the inflammatory drive leading to muscle damage. As such we administered 3 days of IV methylprednisolone followed by 60 mg prednisolone. One week later she was given four days of IV immunoglobulins. She also received IV cyclophosphamide.

For maintenance therapy, methotrexate was given with folic acid, PPI cover and bone protection.

Owing to the swallowing difficulties a radiological guided gastrostomy tube was inserted for nutritional support.

She was discharged to an inpatient rehabilitation unit and finally to home.

Outcome:
Since August 2016 there are no further dermatological manifestations and she remains rash free.  There has been ongoing improvement in her muscle strength such that she is able to rise from a chair without the use of her arms and is independently mobile. Swallow has improved such that she is meeting her nutritional needs orally and no longer requires supplementation via gastrostomy tube.

Unfortunately just 3 months after last clinic review she developed severe and rapidly progressive abdominal swelling and large bilateral PEs. She has now been diagnosed with ovarian teratoma, not previously evident on malignancy screen


Learning Points:

1)    Dermatomyositis is a multisystem disorder.
2)    Early recognition of myositis and treatment can lead to excellent outcomes
3)    TIF1 Gamma antibody is strongly associated with malignancy. The dermatological and muscle disease can pre-date malignancy by 2 years or more.


Discussion
Malignancy
Dermatomyositis and Polymositis are strongly associated with malignant disease, particularly ovarian, cervix, lung, pancreatic, stomach, colorectal and non-Hodgkin lymphoma. In both, incidence of malignant disease is highest at time of myositis diagnosis and for one year afterwards but may arise before, or even > 5 years after diagnosis.[1]

Predictors for low risk (ie good prognostic signs) include, interstitial lung disease, Anti-Mi2 or Antisynthethase. Anti-TIF1-gamma antibody (like in the case of the patient described), Nuclear matrix protein (NMX), older age and dysphagia are associated with increased risk of malignancy and are thus poor prognostic signs.

TIF1-gamma
Recently, it has been revealed that an anti–transcriptional intermediary factor 1 g antibody (TIF1-g-Ab) is frequently detected in the sera of patients with cancer associated myositis (CAM).
Because TIF1-g regulates the tumor growth factor b pathway, it is reported to be related to tumor growth in some malignancies, and may therefore be involved in the key biological mechanisms linking cancers and myositis.

Treatment

Despite the lack of placebo-controlled trials, glucocorticoids are considered the mainstay of initial treatment for idiopathic inflammatory myopathy and myositis-associated interstitial lung disease.  First-line conventional immunosuppressive drugs include either methotrexate or azathioprine, and when they fail, more aggressive therapy includes mycophenolate mofetil, tacrolimus or cyclosporine, intravenous immunoglobulin, rituximab, or cyclophosphamide.[2]
IVIg demonstrated efficacy in DM in a double-blind, controlled trial in 15 patients with refractory DM. In another prospective open-label trial with 35 patients with PM, treatment with IVIg was associated with a significant clinical improvement in 70% of the patients, with stable efficacy reported in half of the patients, 3 years after stopping IVIg. [3]

IM is a multisystem disorder and concern should be given to extramuscular aspects of the disease, particularly the potential for respiratory and cardiac involvement.
Also of relevance is the occurrence of other complicating issues: pain, fatigue, dysphagia and depression.

Written by Dominika Raciborska & Rachelle Shafei

[1] Chinoy et al. The diagnostic utility of myositis autoantibody testing for predicting the risk of cancer-associated myositis. Ann Rheum Dis 2007; 66 (10):1345

[2] Siamak Moghadam-Kia, Rohit Aggarwal, and Chester V Oddis. Treatment of inflammatory myopathy: emerging therapies and therapeutic targets. Expert Rev Clin Immunol. 2015; 11(11): 1265–1275.

[3] Dalakas MC, Illa I, Dambrosia JM, et al. A controlled trial of high-dose intravenous immune globulin infusions as treatment for dermatomyositis. N Engl J Med. 1993;329(27):1993–2000


Thursday, 24 November 2016

Clinical Neuroscience Seminar - Stroke

Tuesday 13th December 

17:30 − 19:00

Room 1.21, Garrod Building




The latest Clinical Neuroscience Seminar covered ischaemic stroke, focussing on clinical presentations, investigation, and management in acutely and in the long-term.



Friday, 11 November 2016

Clinical Neuroscience Seminars: Seizure Disorders


Thanks very much to everyone who came to the first session of our Clinical Neuroscience Seminars (CNS) series. The seminar, on Seizure Disorders, was very well-attended despite some room booking issues. We hope to see you all at the next one, on Stroke and Cerebrovascular Disease, on the 15th of November.

Next Meeting details:
Topic: Head Injury
17.30 - 19.00
15th November 2016
Room 3.06
Garrod Building

https://www.eventbrite.co.uk/e/clinical-neurology-cases-head-injury-tickets-29118944547


Seizure Disorders from Bryan Ceronie


Bryan Ceronie
FY2 Academic Neurology

Friday, 14 October 2016

Anterior choroidal artery syndrome

We saw a 68-year old lady on the ward. She had no past medical history of note.
She presented to hospital with a self-terminating generalised tonic-clonic (GTCS) and in addition was found to have a dense right hemiplegia and expressive dysphasia. The presentation was preceded by a 3-4 week history of increasing confusion and disorientation.

On examination she appeared alert but had significant expressive dysphasia
She was consistently following instructions: 2 and 3 stage commands. There was a subtle ptosis on the left and unequal pupil size. No papilloedema. (Horner’s)
There was a small recent Neurosurgical scar in the right frontal region and a dense right hemiplegia. On further inspection there was wasting of FDIO on the right as well as heberden’s nodes & mild ulnar deviation of the digits. On palpation there was arthralgia in small muscles of the hands, ankle and knee on the right (- ?OA ?RA)
Auscultation of the heart was normal (with normal echocardiogram) and there were no other systemic features (no fever, lymphadenopathy or rash)

Differentials based on clinical findings:
Most likely differential is a vasculitic syndrome leading to ischaemia in the territory of anterior choroidal artery, MCA or internal carotid artery. VZV vasculitis is in the differential as is primary CNS angiitis
Angiocentric lymphoma
Vasculitis secondary to systemic disease such as rheumatoid arthritis
PML could cause this but is usually more indolent
Susacs unlikely as there is no history of headache or hearing deficit
PML would typically follow a more indolent course

Learning points highlighted in discussion of the case:

1. Differentials for confusion/delirium:
-       Drugs
-       Dementia (DLB)
-       Infection (urine and chest most commonly)
-       Head trauma (look for rhinorrhoea, evidence of previous neurosurgery, evidence
-       Hypoxia (ABG)
-       Psychiatric
-       Seizures (non-convulsive, may be secondary to either frontal or temporal seizures. Typically confusion would be fluctuant)
-       Space occupying lesion (papilloedema)
-       Metabolic (Renal failure, Liver failure, electrolyte abnormality)


2. The pathway of the internal carotid artery:
Enters the cranium through the Foramen lacerum, then travels through the
Cavernous sinus. It then turns to travel under the anterior clinoid process emerging just below and posterior to the optic canal. The internal carotid artery finally emerges through the dura just beneath the optic nerve.
There are 5 terminal branches: MCA, ACA, ophthalmic, posterior communicating and anterior choroidal artery. The ophthalmic artery supplies the contents of the orbit and continues forward to supply the central part of the forehead.




3. Syndromes related to anterior choroidal artery infarction
Most commonly patients present with a lacunar syndrome (85%) but there are case studies of confusion and aphasia, presumably where the superficial territory is involved, leading to cortical deficits.

Further reading: Palomeras E, Fossas P, Cano AT, Sanz P, Floriach M. Anterior choroidal artery infarction: a clinical, etiologic and prognostic study. Acta Neurol Scand 2008: 118: 42–47


4. Horner syndrome
Classically the patient will have ptosis, miosis and anhidrosis. There may be mild enophthalmos secondary to lid sagging. There is also increased amplitude of accommodation. Acute features of sympathetic disruption include ipsilateral conjunctival injection and nasal stuffiness.

The precise clinical manifestation depends upon the site of the lesion along the three-neuron sympathetic (adrenergic) pathway, that originates in the hypothalamus:

-       1st order neuron: descends caudally from hypothalamus to the first synapse located in the spinal cord (levels C8-T2). Causes include stroke, demyelination, pituitary or base of skull tumours, basal meningitis, neck trauma, syringomyelia, Arnold chiari malformation and spinal cord tumours.

-       2nd order neuron: travels from sympathetic trunk, through the brachial plexus, over the lung apex and ascends to the superior ganglion, located near the angle of the mandible and bifurcation of the common carotid artery. Causes include apical lung tumours (eg. Pancoast’s), lymphadenopathy (lymphoma, leukaemia, TB), lower brachial plexus trauma, common carotid or subclavian aneurysm, neuroblastoma or mandibular dental abscess.

-       3rd order neuron: ascends within the adventitia of the internal carotid artery, through the cavernous sinous in close relation to CN VI. The oculosympathetic pathway then joins V1. In the orbit the fibres innervate the iris dilator muscle as well as Muller’s muscle (responsible for a small proportion of upper lid elevation and lower lid retraction). This innervation accounts for the minor ptosis (<2mm). Anhidrosis is not a feature of 3rd order lesions as the sympathetic fibre responsible for sweating and vasodilation branch off at the superior cervical ganglion. Causes include cluster headache or migraine, herpes zoster infection, internal carotid artery dissection, carotid-cavernous fistula and temporal arteritis.

Neurological signs can help to localise the lesion:
diplopia, vertigo, ataxia, lateralised weakness à Brainstem
bilat/ipsilat weakness, long tract signs, sensory level, bladder or bowel involvement à Myelopathy
Arm pain/weakness à brachial plexus or lung apex
Ipsilateral ocular paresis & CN VI palsy, no brainstem signs à cavernous sinus
Isolated honers with neck pain àinternal carotid artery dissection

5. Neurological manifestations of rheumatoid arthritis

Manifestations may be either central or peripheral and related to the disease itself or disease modifying treatment.

CNS manifestations: cervical myelopathy (secondary to atlantoaxial subluxation), vasculitis, rheumatoid nodules within the CNS, meningitis and rarely progressive multifocal leucoencephalopathy (risk increased after rituximab therapy) and a hyperviscosity syndrome. Stroke also occurs with increased frequency

PNS manifestations: compression neuropathies (most common, secondary to joint deformities, inflamed synovium, ligaments or compressive tendon sheaths), distal sensory neuropathy, sensori-motor neuropathy or autonomic neuropathy (thought to be secondary to vasculitic process)

Neuromuscular manifestations: myopathy, disuse atrophy, denervation atrophy, myositis.

RA may rarely be complicated by secondary amyloidosis.

Drugs effects:
Nonsteroidal antiinflammatory drugs (NSAIDs) à headaches, drowsiness, and aseptic meningitis
Glucocorticoids à myopathy, depression, psychosis & intracranial hypertension
Gold à peripheral neuropathy, cranial nerve palsies and Guillain-Barré syndr
Methotrexate, Sulfasalazine and leflunomide à headaches.
Leflunomide àperipheral neuropathy
anti-TNF therapies à increase the risk of demyelinating disease


Wednesday, 12 October 2016

Chorea acanthocytosis

Chorea-acanthocytosis

2 cases of patients with speech difficulties, vocal ticks, then progressing to choreiform movements and finally to  dystonias were investigated.

Investigations
Investigations revealed CK of 600-1200.
Neurophysiology showed mild sensory and motor axonal neuropathy, whereas MRI revealed atrophy of caudate and lentiform nucleus.


DaTSCAN showing decreased uptake in the basal ganglia bilaterally

In both cases peripheral blood films revealed acanthocytes. 25% in the first case and 10-70% in the second case.

Diagnostic test showed compound heterozygous mutations in exon 4 (c.0237del, pE80KfsX11) and 72 (c.9429_9432del, p.R3143SfsX5) of VPS13A in case 1 and compound heterozygous mutations in exon 14 (c.1208_1211del, p.Q403RfsX6) and 56 (c.7867C>T, p.R2623X) of VPS13A confirming the suspected diagnosis of chorea-acanthocytosis.

Discussion

Chorea acanthocytosis is a rare autosomal recessive disorder affecting ~1000 worldwide and is caused by mutations in VPS13A gene.
Clincial features include chorea, oromandibular dystonia (which may be mutilating) or generalized dystonia, phonic tics, feeding/ tongue protrusion dystonia, head drops,  ‘rubber man’ gait, seizures, neuropathy and behavioural disturbance (change in personality, OCD, disinhibition). The latter may be a presenting feature.

Diagnosis of chorea-acanthocytosis is primarily clinical with characteristic MRI findings supplied by evidence of muscle disease. MRI and CT might show dilatation of anterior horn of lateral ventricles and atrophy of the caudate nuclei.
Peripheral blood film may show acanthocytes in 5-50% of the red cell population. It has to be noted, however, that in some cases acanthocytosis may appear later or may be absent altogether.  Majority of patients will also have increased creatinine kinase (CK), as exemplified by the two cases described above.
Central nuclei and atrophic fibres will be key findings on muscle biopsy.

There are several causes of neuro-acanthocytosis (oromandibular dystonia as prominent feature ** yes     *perhaps)
•Chorea-acanthocytosis**
•McLeod’s syndrome*
•Huntington’s disease-like type 2
•Pantothenate kinase associated neurodegeneration (PKAN)*
•Hypoprebetalipoproteinaemia, acanthocytosis, retinitis pigmentosa and pallidal degeneration (HARP) syndrome**


McLeod syndrome
McLeod neuroacanthocytosis syndrome is an X-linked recessive (mutations in XK gene) multisystem disorder with haematological, hepatological, neuromuscular and central nervous system involvement in middle-aged males.
Cardiomyopathy and conduction abnormalities as well as dystonia and chorea are a common finding.
Seizures and oromandibular dystonia are, however, less common than in chorea-acanthocytosis.

Oromandibular dystonia
Oromandibular dystonia is characterized by prolonged spasms caused by contraction of the muscles of the mouth and mandible. It involves the muscles of facial expression, mastication, tongue and eyelids.
It can be drug-induced, caused by structural lesions or encephalitis. It may also be genetic (e.g. McLeod syndrome, Ataxia-telangiectasia, Wilson’s and HD).




Summary

The cases described are examples of chorea- acanthocytosis ( of 21 and 18 year disease duration respectively).
Notably, both patients developed parkinsonism after a decade of disease duration and both had abnormal DaTSCANs showing nigrostratial denervation.

Clinically, progressive parkinsonism appears to evolve in later stages of chorea- acanthocytosis and gradually replaces the hyperkinetic abnormal movements, in a manner similar to that observed in Huntington’s disease and other neurodegenerative causes of chorea. The hypothesis of the nigrostriatal pathway being gradually involved in the neurodegenerative process is further supported by the findings of severe loss of dopamine D2-receptor-bearing striatal neurons and loss of dopaminergic projections from the SN to the posterior putamen in a PET study (unconfirmed case).

This phenotypal shift has clinical implications:
•Withdrawal of neuroleptics and tetrabenazine
•L-dopa use may be limited, amantadine reportedly helps gait
•DBS may be useful in some cases




Useful mnemonic: DEPICTING Chorea
D – Drug induced
E – Endocrine
P – Paraneoplastic/polycythaemia vera
I – Infectious/immune mediated
C – Chorea gravidarum
T – Toxic
I – Ischaemic
N – Neonatal hypoxia
G – Genetic

Further Reading
Bohlega S. Chorea-acanthocytosis: clinical and genetic findings in three families from the Arabian peninsula.. Mov Disord. 2003; 18(4): 403-407.

Baeza V et al. Chorea-Acanthocytosis.. Gene Reviews 2002.

In: Pagon RA, Adam MP, Ardinger HH, Wallace SE, Amemiya A, Bean LJH, Bird TD, Fong CT, Mefford HC, Smith RJH, Stephens K, editors. GeneReviews® [Internet]. Seattle (WA): University of Washington, Seattle; 1993-2016. 2002 Jun 14 [updated 2014 Jan 30].
Schneider R, Hoffman HT. Oromandibular dystonia: a clinical report.. J Prosthet Dent. 2011; 106(6): 355-358.