Mario Habek

Novel CCM1, CCM2, and CCM3 mutations in patients with cerebral cavernous malformations: in-frame deletion in CCM2 prevents formation of a CCM1/CCM2/CCM3 protein complex.

Cerebral cavernous malformations (CCM) are prevalent cerebrovascular lesions predisposing to chronic headaches, epilepsy, and hemorrhagic stroke. Using a combination of direct sequencing and MLPA analyses, we identified 15 novel and eight previously published CCM1 (KRIT1), CCM2, and CCM3 (PDCD10) mutations. The mutation detection rate was >90% for familial cases and >60% for isolated cases with multiple malformations. Splice site mutations constituted almost 20% of all CCM mutations identified. One of these proved to be a de novo mutation of the most 3′ acceptor splice site of the CCM1 gene resulting in retention of intron 19. A further mutation affected the 3′ splice site of CCM2 intron 2 leading to cryptic splice site utilization in both CCM2 and its transcript variant lacking exon 2. With the exception of one in‐frame deletion of CCM2 exon 2, which corresponds to the naturally occurring splice variant of CCM2 on the RNA level and is predicted to result in the omission of 58 amino acids (CCM2:p.P11_K68del), all mutations lead to the introduction of premature stop codons. To gain insight into the likely mechanisms underlying the only known CCM2 in‐frame deletion, we analyzed the functional consequences of loss of CCM2 exon 2. The CCM2:p.P11_K68del protein could be expressed in cell culture and complexed with CCM3. However, its ability to interact with CCM1 and to form a CCM1/CCM2/CCM3 complex was lost. These data are in agreement with a loss‐of‐function mechanism for CCM mutations, uncover an N‐terminal CCM2 domain required for CCM1 binding, and demonstrate full‐length CCM2 as the essential core protein in the CCM1/CCM2/CCM3 complex. Hum Mutat 29(5), 709–717, 2008.

Isolated cranial nerve palsies in multiple sclerosis.

Data on patients with multiple sclerosis and cranial nerve involvement as a presenting sign or a sign of disease exacerbation were retrospectively analyzed. Isolated cranial nerve involvement was present in 10.4% out of 483 patients, either as a presenting symptom (7.3%) or a symptom of disease relapse (3.1%). Trigeminal nerve was most frequently involved, followed by facial, abducens, oculomotor and cochlear nerves. Only 54% of patients had brainstem MRI lesion that could explain the symptoms. As multiple sclerosis is a disease characterized by multiple neurological symptoms, while early diagnosis and therapy are critical for the prognosis and course of the disease, the diagnosis of multiple sclerosis should be considered in young adults with cranial nerve involvement.

Nutrition in multiple sclerosis

Multiple sclerosis (MS) is a chronic idiopathic inflammatory demyelinating disease that causes neurological disability in young adults. Etiology of the disease is still unknown, but it has an immune-mediated basis and occurs in genetically susceptible individuals. Nutritional status and dietary habits in MS patients have not been extensively studied or reported, however individual findings suggest that many patients suffer from various forms of malnutrition. In patients with MS, malnutrition has been associated with impairment of the immune system; it affects mental function, respiratory muscle strength and increases a risk of specific nutrient deficiencies. These findings emphasize the need for nutritional support in MS patients. On the other hand, several nutritional compounds have been investigated as a possible treatment in MS, mostly polyunsaturated fatty acids and vitamin D, however their role in the treatment is yet to be confirmed. The aim of this review is to present data on the role of nutritional assessment and treatment in patients with MS.

Enlargement of the spinal cord : Inflammation or neoplasm?

Intramedullary spinal tumours are uncommon lesions that can cause significant difficulties in the differential diagnosis between inflammatory diseases such as multiple sclerosis and acute disseminated encephalomyelitis, and vascular malformations or neoplasms. We report five cases in which the history and the clinical symptoms suggested an inflammatory process of the spinal cord but the MRI characteristics were those of neoplastic lesions. Both non-neoplastic and neoplastic intramedullary lesion may have very similar symptoms, and even CSF abnormalities, but in every one of our cases, a more detailed history and longer observation of the clinical course would have led to the correct diagnosis; in such problem cases, empirical treatment and a follow-up MRI after a months observation would be a more prudent approach providing that the patient is not rapidly deteriorating.

The differential diagnosis of acute transverse myelitis

The clinical and paraclinical characteristics of acute transverse myelitis (ATM) were analyzed in 31 patients. In some patients there was clinical evidence of complete transection, in others of only partial lesions. Magnetic resonance imaging (MRI) in the acute phase in the first group was normal, but showed cord atrophy subsequently. It is probable that the clinical picture was due to parenchymatous neuronal lesions, analogous to those of axonal polyneuropathy. In the patients with incomplete transverse lesions, the most common finding was demyelination. In the patients with circumscribed demyelinating lesions, the symptoms and MRI were suggestive of clinically isolated syndromes (CIS) predictive of multiple sclerosis (MS). Extensive demyelination was indicative of acute disseminated encephalomyelitis (ADEM) due to hyperergic vasculopathy or various forms of chronic vasculitis. In two patients with variable clinical symptoms, a vascular malformation was the cause of the clinical presentation, and in one patient demyelination was due to the disc compression.

Isolated hypoglossal nerve palsy: a diagnostic challenge.

Hypoglossal nerve palsy (HNP) is not an uncommon finding in neurological diseases . However, when isolated, HNP can represent a diagnostic challenge in everyday clinical work and is limited to isolated case reports and few small case series . In this article, we report 4 patients with clinical presentation of isolated HNP due to different etiologies.

Autonomic dysfunction in multiple sclerosis

Multiple sclerosis (MS) is the leading cause of neurological disability in young adults. Since the pathophysiology of MS is characterized by dissemination in space, as well as in time, the autonomic nervous system is inevitably damaged in the course of the disease in many patients and the proportion of affected patients increases with disease duration. Autonomic dysfunction (AD) in MS is explained by lesions in regions responsible for autonomic regulation such as nuclei in the periventricular region of fourth ventricle in the brainstem as well as medullar lesions. Reports about frequency of AD in MS patients vary notably between groups. Nevertheless its impact on quality of life is substantial but, unfortunately, often overlooked. The aim of this article is to present a concise review of various symptoms and signs of autonomic system dysfunction in MS.

The place of the botulinum toxin in the management of multiple sclerosis

Multiple sclerosis (MS) is the most common disabling chronic disease of the central nervous system among young adults. These patients suffer from variety of symptoms that have a profound affect on their working ability, activities of daily living and general quality of life. Treatment of these symptoms is important in order to relief them and improve daily function and quality of life. Many of these symptoms are often resistant to treatment. Botulinum toxin A (BTX) is mainly used for spasticity and bladder dysfunction in MS. It is an effective treatment option for spasticity of the thigh adductor, pes equinus, striatal toe or adductor of the shoulder joint. BTX injections are effective in reducing incontinence episodes and urinary urgency, daytime frequency and nocturia, as well as sustained improvements in quality of life of MS patients with detrusor overreactivity. In addition, BTX is potentially effective in treating pain, trigeminal neuralgia, tremor, neuro-ophthalmologic complications, facial myokymia, gastroparesis, sialorrhea, and hyperhidrosis, however no studies have confirmed its efficacy in MS patients.

Cervical Dystonia Due to Cerebellar Stroke

A 48-year-old woman patient presented with a sudden onset of vertigo, vomiting, and ataxia. On admission, neurological examination revealed horizontal, bidirectional nystagmus and ataxia of the left limbs. Her previous medical history was unremarkable. She smoked 20 cigarettes per day. Emergency MRI findings were consistent with acute cerebellar infarction in the irrigation area of the left superior cerebellar artery (Fig. 1a,b). Standard biochemistry, erythrocyte sedimentation rate, and complete blood count were within the normal limits. Immunologic tests (rheumatoid factor, antineutrophilic cytoplasmic antibodies, anticardiolypin antibodies, antinuclear antibodies) were negative. Chest X-ray and electrocardiogram were normal. Heart ultrasound was normal and did not show signs of patent foramen ovale. Fundus was normal. On the second day of hospital stay, she started developing abnormal posturing of her head along with sustained involuntary contractions of the cervical muscles, and so the head was rotated to the right and down. She was discharged to stationary rehabilitation with almost complete recovery of left limb ataxia. Therapy with aspirin (100 mg) was introduced, and because of registered mild hypertension, ramipril (2.5 mg) in the morning was prescribed. However, involuntary movements progressed severely over the next few weeks, and so she could just temporarily move her head to the normal position, and hypertophy of the left sternocleiodomastoid muscle developed. Neck MRI was normal. Clonazepam (0.5 mg; three times daily) and baclofen (5 mg; three times daily) were introduced. This therapy led to slight improvement of symptoms. One month later, after the application of botulinum toxin, her symptoms improved significantly.

Current concepts in the diagnosis of transverse myelopathies

The clinical symptoms and MRI characteristics of transverse myelopathy (TM) due to non-compressive causes are reviewed, with special emphasis on the differential diagnosis between inflammatory demyelinating lesions, and metabolic and vascular myelopathies. Inflammatory transverse myelopathies are the commonest and most difficult ones to identify. The differentiation between clinically isolated syndromes, multiple sclerosis, neuromyelitis optica, acute disseminated encephalomyelitis and metabolic causes is based on both clinical symptoms and paraclinical signs including magnetic resonance imaging, cerebrospinal fluid analysis, and immunological and biochemical parameters. The most intriguing form of TM is that where there is clinical evidence of complete spinal cord transection, with normal findings in magnetic resonance imaging in the acute phase, but subsequent cord atrophy.