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.


Wednesday, 5 October 2016

ADEM: sinister repercussions of Mycoplasma infection

A case of a patient initially treated for pneumonia and then presenting with generalised progressive  weakness was described.

Examination

On systemic examination she appeared unwell with tachypnoea. There were bilateral crackles to the midzones, a large reducible hernia and pitting oedema up to her shins.

Cranial nerve examination revealed saccadic intrusions of pursuit and right rapid afferent pupilllary defect. Fundoscopy was not possible. Cranial nerves were otherwise intact.
Tone was normal on the right but was increased on the left side. There was reduced power distally in the upper limbs. Lower limb examination revealed reduced power (most marked proximally in hips and knees with both flexion and extension scoring 2/5 with distal power more preserved: plantarflexion scored 4/5 bilaterally). Reflexes were brisk throughout except for ankle reflexes which were 1+ bilaterally), plantar response was extensor.
Sensation to pinprick revealed a sensory level at T8. Vibration sense was intact in the upper limbs but reduced to the knee bilaterally in lower limbs. Proprioception was reduced to ankles bilaterally.
Cerebellar examination revealed dysarthria, dysmetria (with left side being more affected than right) and dysdiadokinesis on the left.

Investigations


MRI Head was compared to the one performed few days later and showed that previous abnormal T2/flair signal in midbrain, superior cerebellar peduncles and at the right middle cerebellar peduncles and pons was less conspicuous in keeping with an evolving inflammatory process.


  

MRI Whole Spine revealed an extensive signal abnormality throughout the lower cervical and thoracic spinal cord with a confluent segment extending from T7-T10 and more patchy involvement in the cervicothoracic cord superiorly.

Microbiology revealed positive CMV and VZV IgG but otherwise no abnormalities. Protein electrophoresis showed polyclonal bands. Autoimmune screen revealed mildly positive pANCA. Haematological investigation showed neutrophilia (WCC 35) and blood film revealed toxic shift (metamyelocytes).
CSF  showed 1 WCC, 123 RBC, 0.26 Protein (normal)


Visual Evoked Potentials showed a well formed response from the left eye with no reproducible response from the right eye.  Somatosensory evoked potentials were normal in the upper limb. Lower limb abnormalities (showing borderline delayed cortical response- P40) could be in keeping with central demyelination.

Differentials

Taking all of the above into consideration a longitudinally extensive transverse myelitis with midbrain/ superior cerebellar peduncle involvement was the pathological process. Neuromyelitis optica (NMO) and Acute Disseminated encephalomyelitis (ADEM) were the top differential diagnoses.

Management

The patient was commenced on 3 day course IVMP followed by oral Prednisolone and a week later transferred to RLH for further investigation and management.
At RLH patient was managed with 4 days of PLEX with weaning of oral steroids. Noticeable neurological improvement was noticed- the patient, who was bedbound on admission and had slurred speech, eventually managed to mobilize with a frame and her speech began to normalise. Full blood count normalized throughout the admission and there were no further temperature spikes.

Diagnosis

Further results were negative for Aquaporin 4, making the diagnosis of NMO less likely. Mycoplasma serology was resulted as positive (1/2560) leading to the diagnosis of ADEM secondary to Mycoplasma Pneumonia. The patient was treated with a 14-day course of Clarithromycin.


Discussion

Acute Disseminated Encephalomyelitis (ADEM) is a widespread acute autoimmune demyelinating disease, which affects brain and spinal cord. Typically, neuroimaging shows multifocal white matter lesions and as such the clinical presentation includes both motor and sensory impairment as well as autonomic dysfunction (in line with presentation of this patient who had reduced power in lower limbs, brisk reflexes and reduced sensation in lower limbs as well as dysarthria and incoordination).

Although incompletely understood, ADEM appears to be triggered by an environmental stimulus in genetically susceptible individuals. Amongst the causes of ADEM the most common is parainfectious but it may be idiopathic or rarely, following vaccination.

Parainfectious ADEM is preceded by a viral or bacterial infectious process. Common bacterial causes include Streptococcus, Mycoplasma pneumoniae and Haemophilia Influenzae. Other associated pathogens include rubella, Epstein-barr virus, herpes simplex virus, human-herpes virus 6, influenza and human immunodeficiency virus.

M. pneumoniae infections can be complicated by neurological disorders, resulting in myelitis, cerebrovascular disorders, servere encephalitis and meningitis. In study conducted by Guleria et al. neurological symptoms were found in 7% of all patients hospitalized for M. pneumoniae.
Antineuronal antibodies have been demonstrated in M. pneumoniae infections with or without CNS disease  (Nishimura et al 1996).

M.pneumoniae may lead to ADEM either by neuroinvasion or immune complex-mediated vasculopathy.

ADEM and the role of neuroinvasion (Stamm et al 2008)

Stamm et al described a case of 45-year-old previously healthy man who presented with fever, cough and non-purulent sputum.  Diagnosis of bilateral basal pneumonia was made and the patient was treated with Clarithromycin. Within 4 days, however, rapidly ascending polyradiculoneuropathy  developed, resulting in facial palsy, opththalmoplegia and tetraparesis. Viral PCR and bacterial and viral serology were negative.
CT head showed brain oedema and inflammatory/ demyelinating lesions in the subcortical white matter, whilst EMG revealed severe peripheral neuropathy.
No antiganglioside (GM) 1 or anti-GM2 antibodies were discovered.
Differential diagnoses included polyradiculoneuropathy (atypical Guillain-Barré syndrome) and acute encephalitis as complications of bilateral pneumonia caused by M. pneumoniae. The patient was commenced on Clarithromycin with Amoxicillin and Ceftriaxone  then given IVIG (0.4 g/ kg bodyweight/day for 5 days).
He died of intractable cerebral edema 10 days after the onset of neurologic symptoms.  At Autopsy M. pneumoniae RNA detected in brain tissue by nucleic acid hybridization.
The case suggests a role of invasion of the CNS by the organism itself. Interestingly, neuroinvasion is more prevalent in patients with early onset neurologic complications. The effects of the neuroinvasion, however, remain unclear. The organism may either cause direct damage or trigger a more violent immunologic reaction.

Parainfectious ADEM (Gupta et al 2007)

A 41-year-old man presented with a 2-week history of lethargy, chills, nausea, vomiting and a productive cough. CT Chest showed right lower lobe pneumonia and the patient was commenced on IV Amoxicillin and Doxycycline.
One week later he developed lower limb weakness, which progressed to complete paraplegia with urinary retention. Six days later patchy visual loss in both eyes follows and fundoscopy revealed swollen optic disc bilaterally.
Serology suggested recent Mycoplasma pneumoniae infection with a M. pneumoniae agglutination antibody titre of 1 in 1280.
MRI showed increased T2 signal and swelling of the cord extending from T3 to T8, as well as several white matter lesions in the periventricular white matter of the cerebral hemispheres, whereas CSF revealed a mononuclear pleocytosis of 24 mononuclear cells per microlitre.
A diagnosis of acute disseminated encephalomyelitis (ADEM) secondary to M. pneumoniae was made and patient was commenced on IV methylprednisolone was commenced at 1 g daily.  This resulted in no improvement over the course of the next three days, so treatment was changed to high-dose oral prednisolone and plasma exchange.
A total of 10 exchanges were carried out over 3 weeks. This resulted in improved vision and the patient regaining normal lower limb power and sphincter control over the next two months.
This dramatic response to plasma exchange supports a hypothesis that the ADEM was secondary to an immune complex-mediated vasculopathy


Key points

Neurologic manifestations occur approximately ten days after the onset of the initial respiratory tract infection

CSF: CSF Gram stain and bacterial cultures are usually negative. The CSF leukocyte count is elevated predominantly mononuclear pleocytosis and most cases of M. pneumoniae-associated ADEM have a normal CSF/serum glucose ratio.
Serology or PCR: IgM antibodies can be detected shortly after the acute infection, may persist for up to 6 months and are followed by IgG titer elevation.
A positive cold haemagglutinins titer (non-specific)

MRI Head/ Spinal Cord:  characteristic findings: patchy asymmetric or diffuse signal changes of gray and white matter and multifocal, asymmetric foci of high signal intensity on flair and T2 weighted images.

Management: Antibiotic therapy has been temporally associated with clinical improvement in some cases of M. pneumoniae-associated ADEM/ATM
Corticosteroids are useful in the initial management of ADEM and transverse myelitis with their main contribution being the shortening of the duration of neurologic findings (only if no infective source identified).
Intravenous immune globulin is usually used in case of no response to steroids.
Last therapeutic measure: Plasma Exchange

In this case:
Patient presented with worsened neurology (cerebellar and thoracic spine involvement) after a severe chest infection. Blood tests were unremarkable except for Mycoplasma serology. This shows the importance of translating a wide differential into investigations.



References and recommended reading
1.Garg R K. Acute disseminated encephalomyelitis. Postgrad Med J 2013; 79(): 11-17.
2. Ning MM, Smirnakis S, Furie KL, Sheen VL. Adult acute disseminated encephalomyelitis associated with poststreptococcal infection. J Clin Neurosci. 2005;12:298–300.
3. Sotgiu S, Pugliatti M, Rosati G, Deiana A, Sechi P. Neurological disorders associated with Mycoplasma pneumoniae infection. Eur J Neurol 10: 165-168, 2003.

4. Guleria R, Nisar N, Chawla TC, Biswas NR. Mycoplasma pneumoniae and central nervous system complications: a review. J Lab Clin Med 146: 55-63, 2005.
5.  Höllinger P, Sturzenegger M, Mathis J, Schroth G, Hess CW. Acute disseminated encephalomyelitis in adults: a reappraisal of clinical, CSF, EEG, and MRI findings. J Neurol. 2002;249:320–9.
6. Beleza P, Ribeiro M, Pereira J, Ferreira C, Jordão MJ, Almeida F. Probable acute disseminated encephalomyelitis due toHaemophilus influenzae meningitis. Dev Med Child Neurol. 2008;50:388–91
7. Stamm B, Moschopulos M, Hungerbuehler H, Guarner J, Genrich GL, Zaki SR. Neuroinvasion by Mycoplasma pneumoniae in acute disseminated encephalomyelitis. Emerg Infect Dis. 2008;14(4):641-3
8. Gupta A, Kimber T, Crompton JL, Karagiannis A. Acute disseminated encephalomyelitis secondary to Mycoplasma pneumoniae. Intern Med J. 2009 Jan;39(1):68-9
9. Tsiodras S, Kelesidis T, Kelesidis I, Voumbourakis K, Giamarellou H. Mycoplasma pneumoniae-associated myelitis: a comprehensive review. Eur J Neurol. 2006 Feb;13(2):112-24.

10. Nishimura M, Saida T, Kuroki S, Kawabata T, Obayashi H, Saida K, Uchiyama T. Post-infectious encephalitis with anti-galactocerebroside antibody subsequent to Mycoplasma pneumoniae infection. J Neurol Sci. 1996 1;140(1-2):91-5.